Process for preparing pyrano[3,4-b]indole or thio pyrano[3,4-b]indole derivatives

ABSTRACT

Indole derivatives characterized by having a 1,3,4,9-tetrahydropyrano[3,4-b]indole or 1,3,4,9-tetrahydrothiopyrano[3,4-b]indole nucleus bearing a substituent in position 1, said substituent incorporating an acid, ester or amide function therein, are disclosed. The nucleus is further substituted at position 1 and may be optionally substituted at positions 3, 4, 5, 6, 7, 8, and 9. The derivatives are useful antiinflammatory, analgesic, antibacterial and antifungal agents and methods for their preparation and use are also disclosed.

This application is a continuation-in-part of our earlier-filedapplication Ser. No. 513,693, filed Oct. 10, 1974, now U.S. Pat. No.3,974,179 issued August 10, 1976, which is a continuation-in-part of ourearlier-filed application Ser. No. 311,023, filed Nov. 30, 1972, nowabandoned, which is a continuation-in-part of our earlier-filedapplication Ser. No. 289,714, filed Sept. 15, 1972 now U.S. Pat. No.3,939,178 issued Feb. 17, 1976 which is a continuation-in-part of ourearlier-filed application Ser. No. 148,895, filed June 1, 1971 (now U.S.Pat. No. 3,843,681, issued Oct. 22, 1974).

BACKGROUND OF THE INVENTION

This invention relates to novel indole derivatives, to processes fortheir preparation and to intermediates used in these processes.

Notwithstanding the advances made during the last four decades in thedevelopment of agents for the treatment of inflammatory conditions,there still remains a need for effective agents without the side effectsassociated with the therapeutic agents presently used for this purpose.

The indole derivatives of this invention have been found to exhibitinteresting and useful pharmacodynamic properties without elicitingundesirable side effects. Notable attributes of this effect areantiinflammatory and analgesic activities. In addition the compounds ofthis invention exhibit antibacterial and antifungal properties.

SUMMARY OF THE INVENTION

The indole derivatives of this invention are characterized by having apyrano[3,4-b] indole or thiopyrano[3,4-b] indole nucleus bearing asubstituent at position 1, said substituent incorporating an acid, esteror amide function therein. These derivatives may be represented byformula I ##STR1## in which R¹ is selected from the group consisting oflower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl,benzyl and 2-thienyl, R², R³, R⁴ and R⁵ are the same or different andare each selected from the group consisting of hydrogen and lower alkyl,R⁶ is selected from the group consisting of hydrogen, lower alkyl, lowercycloalkyl, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, phenyl,nitro, halo, mercapto, lower alkylthio, trifluoromethyl, amino andsulfamoyl, R⁷ is selected from the group consisting of hydrogen, loweralkyl and lower alkenyl, X is selected from the group consisting of oxyand thio, Y is selected from the group consisting of carbonyl, ##STR2##in which each of R⁸, R⁹, R¹⁰,R¹¹, R¹² and R¹³ is hydrogen or loweralkyl, and Z is selected from the group consisting of hydroxy, loweralkoxy, amino, lower alkylamino, di(lower)alkylamino and phenylamino.

Also included within the scope of this invention are pyrano[3,4-b]indole and thiopyrano[3,4-b] indole derivatives of formula I in which R⁶represents from one to four substituents, which may be presentsimultaneously, at positions 5,6,7 and 8 thereof. The exact nature ofsuch substituents does not have to be limited necessarily by the abovedefinitions of R⁶, and R⁶ may also include additional definitions, forexample, mercapto, lower alkylthio, trifluoromethyl and otherhalo(lower)alkyls, amino and sulfamoyl, provided that any two suchsubstituents do not interfere with each other. Accordingly, the indolederivatives of this invention are represented also be general formula Ia##STR3## in which R¹, R², R³, R⁴, R⁵, R⁷, X, Y and Z are as defined inthe first instance and R^(6a), R^(6b), R^(6c) and R^(6d) are the same ordifferent and each is selected from the group consisting of hydrogen,lower alkyl, lower cycloalkyl, hydroxy, lower alkoxy, benzyloxy, loweralkanoyloxy, phenyl, nitro, halo, mercapto, lower alkylthio,trifluoromethyl, amino and sulfamoyl.

The indole derivatives of this invention of formula I are prepared byreacting a compound of the formula ##STR4## in which R², R³, R⁴, R⁵, R⁶and R⁷ are as defined in the first instance and X' is hydroxy ormercapto with a compound of formula ##STR5## in which R¹, Y and Z are asdefined in the first instance, in the presence of an acid catalyst.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein contemplates both straight andbranched chain alkyl radicals containing from one to six carbon atomsand includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,2-methylpentyl and the like.

The term "lower alkenyl" as used herein contemplates both straight andbranched chain alkenyl radicals containing from two to six carbon atomsand includes vinyl, allyl, 1-propenyl, methallyl, 2-ethyl-3-butenyl andthe like.

The term "lower alkynyl" as used herein contemplates both straight andbranched chain alkynyl radicals containing from two to six carbon atomsand includes ethynyl, propargyl, 1,1-dimethylpropargyl and the like.

The term "lower cycloalkyl" as used herein contemplates saturated cyclichydrocarbon radicals containing from three to six carbon atoms andincludes cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term "lower alkoxy" as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to four carbon atomsand includes methoxy, ethoxy, isopropoxy and the like.

The term "lower alkanoyloxy" as used herein contemplates both straightand branched chain alkanoyloxy radicals containing from two to sixcarbon atoms and includes acetoxy, propionyloxy, hexanoyloxy and thelike.

The term "halo" as used herein contemplates halogens and includesfluorine, chlorine, bromine and iodine.

Where the term "lower" is used herein as part of the description ofalkylamino and dialkylamino, it contemplates one to six carbon atoms foreach alkyl group of such a radical and includes methylamino,n-hexylamino, dimethylamino, diethylamino and the like.

The indole derivatives of formula I in which Z is hydroxy, the acidcompounds of this invention, form addition salts with suitable inorganicand organic bases. These salts possess the same activities as the parentacid compound when administered to animals and may be utilized in thesame manner. Suitable bases to form these salts include, for example,the hydroxides, lower alkoxides, carbonates and bicarbonates of sodium,potassium, calcium and magnesium, as well as the bases, ammonia,triethylamine, benzylamine and the like. The addition salts thusobtained are the functional equivalents of the parent acid compound inrespect to their therapeutic use. Hence, these addition salts areincluded within the scope of this invention and are limited only by therequirement that the bases employed in forming the salts bepharmaceutically acceptable.

Also included within the scope of this invention are the isomers of thecompounds of formula I resulting from the asymmetric centers containedtherein.

ANTIINFLAMMATORY AND ANALGESIC ACTIVITY

The useful antiinflammatory and analgesic activities of the indolederivatives of this invention may be demonstrated in standardpharmacologic tests, for example, the tests described by R. A. Turner in"Screening Methods in Pharmacology", Academic Press, New York andLondon, 1965, pp. 152-163 and pp. 100-117, respectively.

More particularly, the antiinflammatory activity of the compounds ofthis invention may be readily demonstrated in a modification of theFreund's adjuvant test, the adjuvant induced acute edema test asdescribed by J. R. Boissier, et al., Therapie, 25, 43 (1970). This testis known to correlate well with data derived from clinical results withhumans. Boissier et al. have demonstrated this correlation with suchclinically active compounds as phenylbutazone, mefenamic acid,indomethacin, aspirin, hydrocortisone and prednisolone.

More particularly exemplified, a substantial antiinflammatory effect forthe compounds listed below is demonstrable at oral doses of 100 mg/kg orless in this acute edema test. In this test male rats are treated withthe test compound one hour before the injection of Freund's adjuvantinto the paw (day 0). The rats are then treated with the same dose ofthe test compound for the next 3 days. The antiinflammatory effect ofthe test compound is measured by the reduction of pedal inflammation,see Turner cited above, and expressed as a percent inhibition fromadjuvant injected control rats on day 3.

    __________________________________________________________________________                               DAILY                                                                         DOSE  PERCENT                                               COMPOUND          (MG/KG)                                                                             INHIBITION                                   __________________________________________________________________________    1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                     indole-1-acetic acid, Example No. 1                                                                      100   30                                           1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                      indole-1-acetic acid, Example No. 15                                                                     100   47                                           1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                     indole-1-acetic acid, Example No. 16                                                                     100   40                                           8-methyl-1-propyl-1,3,4,9-tetrahydropyrano-                                   [3,4-b]indole-1-acetic acid, Example No. 26                                                              100   44                                           1-butyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                      indole-1-acetic acid, Example No. 25                                                                     100   40                                           1-t-butyl-1,3,4,9-tetrahydropyrano[3,4-b]-                                    indole-1-acetic acid, Example No. 24                                                                     100   30                                           5-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]-                            indole-1-acetic acid, Example 32                                                                         100   44                                           1-ethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]-indole-                           1-acetic acid, Example No. 98                                                                             25   32                                           __________________________________________________________________________

The lack of side effects for the compounds of this invention may bedemonstrated by standard acute toxicity tests (see Turner cited above)and by prolonged administration of the compound to warm-blooded animals.

When the present indole derivatives of this invention are employed asantiinflammatory and analgetic agents in warm-blooded animals, e.g.,rats, they may be administered orally, alone or in dosage forms, i.e.,capsules or tablets, combined with pharmacologically acceptableexcipients, such as starch, milk sugar and so forth. They may also beadministered orally in the form of solutions in suitable vehicles suchas vegetable oils.

The dosage of the indole derivatives of this invention will vary withthe particular compound chosen and form of administration. Furthermore,it will vary with the particular host under treatment. Generally, thecompounds of this invention are administered at a concentration levelthat affords protective effects without any deleterious side effects.These antiinflammatorily-analgesically effective concentration levelsare usually obtained within a therapeutic range of 1.0 mg to 500 mg/kgper day, with a preferred range of 10 to 100 mg/kg per day.

ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY

The indole derivatives of this invention also exhibit utility asantibacterial agents against a number of gram-positive and gram-negativemicroorganisms, such as, Staphylococcus pyogenes, both penicillinsensitive and penicillin resistant, Streptococcus faecalis, Escherichiacoli, Aerobacter aerogenes, Salmonella pullorum, Pseudomonas aerugenosa,Proteus mirabilis, Proteus vulgaris, Klebsiella pneumoniae and Serratiamarcescens and as antifungal agents against a number of pathogenic fungisuch as, Candida albicans, Microsporum gypseum and Trichophytongranulosum, in standard tests for antibacterial and antifungal activity,such as those described in "Antiseptics, Disinfectants, Fungicides andSterilization", G. F. Reddish, Ed., 2nd ed., Lea and Febiger,Philadelphia, 1957 or by D. C. Grove and W. A. Randall in "Assay Methodsof Antibiotics", Med. Encycl. Inc., New York 1955.

For example, by employing a test like the serial broth dilution test,see Grove and Randall, cited above, in which dilutions of the compoundsof this invention in nutrient broth are inoculated with themicroorganisms or fungi, described above, incubated at 37° C. for 2days, respectively, and examined for the presence of growth, it may beshown that 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-propionicacid is able to inhibit growth totally in this system of Proteusvulgaris, Klebsiella pneumoniae and Serratia marcescens at aconcentration of 100 mcg/ml. or less.

When the compounds of this invention are employed as antibiotic orantifungal agents in warm-blooded animals, e.g. rats, they may beadministered alone or in combination with pharmacologically acceptablecarriers. The proportion of the compound is determined by the solubilityand chemical nature of the compound, chosen route of administration andstandard biological practice. For example, they may be administeredorally in solid form containing such excipients as starch, milk sugar,certain types of clay and so forth. They may also be administered orallyin the form of solutions or they may be injected parenterally. Forparenteral administration they may be used in the form of a sterilesolution containing other solutes, for example, enough saline or glucoseto make the solution isotonic.

The dosage of the present therapeutic agents as antibiotic or antifungalagents will vary with the form of administration and the particularcompound chosen. Furthermore, it will vary with the particular hostunder treatment. Generally, treatment is initiated with small dosagessubstantially less than the optimum dose of the compound. Thereafter,the dosage is increased by small increments until the optimum effectunder the circumstances is reached. In general, the compounds of thisinvention are most desirably administered at a concentration level thatwill generally afford antibacterially or antifungally effective resultswithout causing any harmful or deleterious side effects and preferablyat a level that is in a range of from about 1.0 mg. to about 1000 mg.per kilo per day, although as aforementioned variations will occur.However, a dosage level that is in the range of from about 10 mg. toabout 500 mg. per kilo per day is most desirably employed in order toachieve effective results.

In addition, the agent may be employed topically. For topicalapplication they may be formulated in the form of solutions, creams, orlotions in pharmaceutically acceptable vehicles containing 0.1-5percent, preferably 2 percent, of the agent and may be administeredtopically to the infected area of the skin.

Also the antibacterial properties of the compounds of this invention maybe utilized for washing equipment in hospitals, homes and farms,instruments used in medicine and bacteriology, clothing used inbacteriological laboratories, and floors, walls and ceiling in rooms inwhich a background free of gram-positive and gram-negativemicroorganisms, such as those listed above, is desired. When employed inthis manner the compounds of this invention may be formulated in anumber of compositions comprising the active compound and an inertmaterial. In such compositions, while the compounds of formula I of thisinvention may be employed in concentrations as low as 500 p.p.m., from apractical point of view, it is desirable to use from about 0.10% byweight, to about 5% by weight or more.

The formulations that may be used to prepare antiseptic wash solutionsof the compounds of this invention are varied and may readily beaccomplished by standard techniques, see for example, "Remington'sPractice of Pharmacy", E. W. Martin et al., Eds., 12th ed., MackPublishing Company, Easton, Penn., 1961, pp. 1121-1150. In general, thecompounds may be made up in stock solutions. They can also be formulatedas suspensions in an aqueous vehicle. These make useful mixtures fordecontaminating premises. Also, aqueous vehicles containing emulsifyingagents, such as sodium lauryl sulfate, and relatively highconcentrations, e.g., up to about 5% by weight, of the compounds may beformulated by conventional techniques.

A typical antiseptic preparation useful for disinfecting floors, walls,ceiling, and articles in a contaminated room may be prepared by adding 5to 25 g. ofN,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide to amixture of 150 to 300 g. of polyethylene glycol 1540 and 150 to 300 g.of polyethylene glyol 300. The resulting mixture is stirred while asolution of 1 to 10 g. of sodium lauryl sulfate in 300 to 400 ml. ofwater is added portionwise. The article to be disinfected is coated orimmersed in the preparation for a prolonged time, for example, one hour,and then rinsed with sterile water.

PREPARATION OF INDOLE DERIVATIVES

For the preparation of the indole derivatives of this invention weprefer to use as starting materials the compounds of the general formulaII. ##STR6## in which R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in thefirst instance and X' is hydroxy or mercapto.

The starting materials of formula II in which X' is hydroxy are eitherknown, for example, tryptophol, described by H. R. Snyder and F. J.Pilgrim, J. Am. Chem. Soc. 70, 3770 (1948), or they may be obtained bythe following process: ##STR7##

With reference to this process phenylhydrazines of formula III and thehydroxyaldehyde of formula IV are reacted together according to theconditions of the "Fischer Indole Synthesis", for example, see P. L.Julian, E. N. Myer and H. C. Printy, "Heterocylic Compounds", R. C.Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc., New York, 1952, pp.8-11, to form the desired starting material (II, X' = OH).

The phenylhydrazines of formula III are either known or may be preparedaccording to known methods. A convenient method involves thediazotization of the appropriately substituted aniline to give thecorresponding diazo derivative. The latter compound is then reduced withstannous chloride or sodium sulfite to give the correspondingphenylhydrazine, see L. F. Fieser and M. Fieser, "Advanced OrganicChemistry", Reinhold Publishing Corporation, New York, 1961, p. 734.

The hydroxyaldehydes of formula IV are either known, see for example,"Rodd's Chemistry of Carbon Compounds," S. Coffey, Ed., Vol. I d, 2nded., Elsevier Publishing Co., Amsterdam, 1965, pp. 44-49, or they may beprepared according to known methods. A convenient method involvesreduction of an appropriate lactone of formula ##STR8## withbis-(3-methyl-2-butyl)borane, H. C. Brown and D. B. Bigley, J. Am. Chem.Soc., 83, 486 (1961) ,diisobutyl aluminum hydride, L. I. Zakharkkin andI. M. Khorlina, Tetrahedron Letters, 619 (1962) or sodium aluminumhydride, L. I. Zakharkin et. al., Tetrahedron Letters, 2087 (1963). Theappropriate lactones utilized in this reduction are either commerciallyavailable, for example, δ-valerolactone, α-methyl-butyrolactone, or theyare described with a variety of methods for their preparation in organicchemistry textbooks; such as the textbooks, "Methoden der OrganischenChemie", Houben-Weyl, E. Muller, Ed., Vol. VI/2, Georg Thieme Verlag,Stuttgart, 1963, pp. 561-852 or L. F. Fieser and M. Fieser, "AdvancedOrganic Chemistry", cited above.

Alternatively, the starting materials of formula II in which R², R³, R⁴and R⁷ are hydrogen and X' is hydroxy may be prepared by lithiumaluminum hydride reduction, N. G. Gaylord, "Reduction with Complex MetalHydrides", Interscience Publishers, Inc., New York, 1956, pp. 322-370,of compounds of formula V described by T. Y. Shen, U.S. Pat. No.3,161,654, Dec. 15, 1964: ##STR9## wherein R¹⁵ is lower alkyl and R⁵ andR⁶ are as defined in the first instance.

The starting materials of formula II in which X' is mercapto and R², R³,R⁴, R⁵, R⁶, and R⁷ are as defined in the first instance may be obtainedby the following process: The appropriate compound of formula II (X' =OH), described above, is treated with phosphorus tribromide in an inertsolvent, for example, ether or carbon tetrachloride, to afford thecorresponding 3-(2-bromoethyl)indole derivative. The latter compound isthen converted to the desired starting material of formula II (X' = SH)by a procedure similar to that described by N. N. Suvorov and V. N.Buyanov, Khim.-Farm. Zh., l, 4 (1967), [Chem. Abstr. 67, 73474a (1967)],for converting 3-(2-bromoethyl)indole to indole-3-ethanethiol (II; R²,R³, R⁴, R⁵ R⁶ and R⁷ = H and X' = SH). Accordingly, the appropriate3-(2-bromoethyl)indole derivative is treated with sodium or potassiumthiosulfate to afford the corresponding sodium or potassiumβ-(3-indolyl)ethyl thiosulfate derivative, respectively, which ontreatment with strong alkali for example, sodium or potassium hydroxide,is transformed into the corresponding bis-[ω-(3-indolyl)ethyl]disulfidederivative. Reduction of the latter compound with lithium aluminumhydride gives the desired compounds of formula II.

It should be noted that the preceding process is not entirely practicalfor the preparation of the compounds of formula II in which X' ismercapto and R⁶ is hydroxy or lower alkanoyloxy. For this reason, thepreferred starting materials of formula II for the ultimate preparationof the compounds of formula I in which R⁶ is hydroxy or loweralkanoyloxy and X is thio are the corresponding compounds of formula IIin which R⁶ is benzyloxy, readily prepared by this process. When thelatter compounds are used as starting materials in this manner, they arefirst subjected to the process (II + VI → VII), described below.Subsequently, the benzyloxy group is removed by hydrogenation, in thepresence of a catalyst, for example, 10% palladium on carbon, to affordthe corresponding compound of formula I in which R⁶ is hydroxy. Thelatter may be converted if desired to the corresponding compound offormula I in which R⁶ is lower alkanoyloxy by conventional means, forexample, by treatment with the appropriate lower alkanoic anhydridepreferably in the presence of pyridine. Likewise, it should be notedthat similar use of the starting materials of formula II in which X' ishydroxy and R⁶ is benzyloxy to obtain the corresponding compound offormula I in which R⁶ is hydroxy or lower alkanoyloxy is preferred.

For the preparation of the acid and ester compounds of this invention offormula I in which Z is hydroxy or lower alkoxy and R¹, R², R³, R⁴, R⁵,R⁶, R⁷, X and Y are as defined in the first instance, we have found thatthe following, hitherto undisclosed process is both practical andconvenient: ##STR10## in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Y, and Zare as defined in this instance, X' is hydroxy or mercapto and R¹⁶hydrogen or lower alkyl. (For convenience and clarity these particularacid and ester compounds of formula I are represented above as formulaVII).

With reference to the above scheme the starting material of formular IIis condensed with a ketoacid (VI, R¹⁶ = H) or a ketoester (VI, R¹⁶ =lower alkyl) in the presence of a suitable acid catalyst to yield thecompounds of formula VII. formula

Generally comparable yields of product are obtained in this process wheneither the ketoacid or the corresponding ketoester is used. However, inthe case where it is desired to prepare acid compounds of formula VII inwhich Y is ##STR11## and R¹⁶ is hydrogen, it is preferable with respectto yield to first condense the appropriate β-ketoester of formula VIrather than the corresponding β-ketoacid and then hydrolyze theresulting ester product to give the desired acid compound.

Moreover, in the general practise of this invention it is often moreconvenient to prepare the acid compounds of formula VII by using theketoester instead of the ketoacid in this process and then hydrolyze theresulting ester product to the desired acid, the reason being simplythat the ketoesters are generally more readily available eithercommercially or by synthesis.

The hydrolysis of compounds of formula VII in which R¹⁶ is lower alkylto their corresponding acids of formula VII is readily effected bytreatment with a suitable alkali, for example, potassium hydroxide orsodium carbonate, in aqueous methanol or aqueous ethanol.

In practising the condensation (II + VI→VII) we have found it preferableto use a solvent as a reaction medium. Any solvent inert to the reactionconditions may be used. Suitable solvents include benzene, toluene,diethyl ether, dioxan, tetrahydrofuran, methylene dichloride, carbontetrachloride and the like. Benzene and tetrahydrofuran are especiallyconvenient and practical for this use. A variety of suitable acidcatalysts may be used for this condensation, for example, the type ofcatalyst used in a Friedel-Crafts Reaction, i.e. p-toluenesulfonic acid,phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloricacid and sulfuric acid and the like. p-Toluenesulfonic acid, borontrifluoride and phosphorus pentoxide are included among the preferredacid catalysts. The amount of acid catalyst used is not especiallycritical and may range from 0.01 molar equivalents to 100 molarequivalents; however, a range of from 0.1 to 10 molar equivalents isgenerally preferred. The time of the reaction may range from 10 minutesto 60 hours, with the preferred range being from one-half to 24 hours.The temperature of the reaction may range from -20° C. to the boilingpoint of the reaction mixture. Preferred temperature ranges include 20°to 120° C.

The α-, β-, γ- and δ-ketoacids and -ketoesters of formula VI are eitherknown, for example, ethyl pyruvate, levulinic acid, ethylα,α-dimethylacetoacetate, β,β-dimethyllevulic acid and benzoylaceticacid or they may be prepared by known methods described in generalorganic chemistry textbooks. For example, a comprehensive review on theproperties and preparation of such α-, β-, γ- and δ-ketoacids and-ketoesters may be found in "Rodd's Chemistry of the Carbon Compounds",cited above, Vol. 1d, pp. 226-274.

Alternatively, the acid compounds of formula I in which Z is hydroxy andR¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instancemay be prepared by the following process: ##STR12## in which Y' is CH₂,C(R⁸)(R⁹)CH₂, C(R⁸)(R⁹)C(R¹⁰)(R¹¹)CH₂ orC(R⁸)R⁹)C(R¹⁰)(R¹¹)C(R¹²)(R¹³)CH₂, R¹⁷ is hydrogen or lower alkyl, Z ishydroxy and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in thefirst instance.

With reference to this alternative process a starting material offormula II is condensed with an acylated ketoalcohol (VIII) in thepresence of a suitable acid catalyst according to the conditionsdescribed above for the condensation (II + VI→VII). The ketoalcohollower alkyl esters are either known, for example, acetonyl acetate or5-acetoxypentan-2-one, or may be prepared by known methods, forinstance, see "Rodd's Chemistry of the Carbon Compounds", cited above,Vol. 1d, pp. 49-54. In this manner the condensation product of generalformula IX is obtained. Hydrolysis of this product with an aqueousalcoholic solution of a suitable alkali, for example, sodium hydroxidein aqueous methanol, affords the corresponding primary alcohol X. Theprimary alcohol is then oxidized to the corresponding aldehyde offormula XI. Although a variety of methods are known for the oxidation ofa primary alcohol to its corresponding aldehyde, see for example,"Rodd's Chemistry of the Carbon Compounds", cited above, Vol. 1c, pp.4-10, we have found that the method of K. E. Pfitzner and J. G. Moffat,J. Am. Chem. Soc., 87, 5670 (1965) using N,N-dicyclohexylcarbodiimideand dimethyl sulfoxide in the presence of a suitable acid, for example,trifluoroacetic acid, to be both efficacious and convenient in thiscase. Subsequently the aldehyde XI may be converted to the desired acidcompounds of formula I by a variety of oxidizing agents, includingsilver oxide, alkaline permanganate, hydrogen peroxide, peracids and thelike. In this case we prefer to use silver oxide according to the methodof M. Delepine and P. Bonnet, Compt. rend., 149, 39 (1909).

The amide compound of this invention of formula I in which Z is amino,lower alkylamino, di(lower)alkylamino and phenylamino and R¹, R², R³,R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance, may beprepared from their corresponding acid compounds of formula I (compoundsof formula VII in which R¹⁶ is hydrogen, described above) by treatmentof the latter compounds with a lower alkyl chloroformate, preferablyethyl chloroformate, in the presence of triethylamine, affording thecorresponding mixed anhydride, which is converted by treatment with theappropriate amine, such as ammonia, aniline or a suitable alkylamine ordialkylamine, to the desired amide compound of formula I.

Alternatively, these amides of formula I may be prepared from thecorresponding esters of formula I (compounds of formulae VII, in whichR¹⁶ is lower alkyl, described above) by treatment of the lattercompounds with the appropriate amine according to known methods, forexample, see A. L. J. Beckwith in "The Chemistry of Amides", J. Zalicky,Ed., Interscience Publishers, New York, 1970, pp. 96-105.

Again alternatively, the amide compounds of formula I in which Z isamino, lower alkylamino, di(lower)alkylamino, and phenylamino and R¹,R², R³, R⁴, R⁵, R⁶, R⁷, X and Y are as defined in the first instance,may be prepared by the condensation of an appropriate starting materialof formula II with an appropriate α-, β-, γ- or δ-ketoamide in thepresence of a suitable acid catalyst according to the conditionsdescribed above for the condensation (II + VI→VII). The ketoamidesrequired for this condensation are either known, for example, pyruvamideor α,α-dimethylacetoacetamide, or they may be prepared by known methods,for instance, see "Rodd's Chemistry of the Carbon Compounds", citedabove, Vol. 1d, pp. 226-274.

The alkylated acid and ester compounds of this invention of formula I inwhich R⁷ is lower alkyl or lower alkenyl and Z is hydroxy or loweralkoxy, are prepared readily from the above described, correspondingacid or ester compounds of formula I in which R⁷ is hydrogen. Thisconversion involving the N-alkylation of the indolic nitrogen iseffected by treatment of the latter compounds with an appropriate loweralkyl or lower alkenyl halide in an inert solvent in the presence of anacid acceptor. Preferred conditions for effecting this conversioninclude the use of sodium hydride as an acid acceptor andtetrahydrofuran as the inert solvent.

The N-alkylated amide compounds of formula I in which R⁷ is lower alkylor lower alkenyl and Z is amino, lower alkylamino, di(lower)alkylaminoor phenylamino are preferably prepared by either treatment of theN-alkylated acid compounds of formula I, described above, with a loweralkyl chloroformate followed by treatment with the appropriate amine, ortreatment of the N-alkylated ester compounds of formula I, describedabove, with an appropriate amine, in the manner described previously forthe preparation of the amide compounds of formula I in which R⁷ ishydrogen.

Finally, it is the intention to cover all changes and modifications ofthe embodiment of the invention herein chosen for the purpose ofdisclosure which are within the scope and spirit of this invention. Suchchanges and modification include those variations which depend on wellknown interconversions of acids and esters or alternation of the orderof N-alkylation in the processes disclosed herein.

For example, in preparing the N-alkylated acid, ester or amide compoundsof formula I in which R⁷ is lower alkyl or lower alkenyl, the changingof the order of the N-alkylation step, as depicted in the embodiment ofthis invention, by the act of N-alkylation of the starting materials offormula II and subjecting the products thereof to treatment with anappropriate ketoacid or ketoester of formula VI or a ketoamide,according to the teaching of the present disclosure, would not departfrom the spirit or scope of this invention.

Likewise, the preparation of the N-alkylated amide compounds of formulaI in which R⁷ is lower alkyl or lower alkenyl and Z isdi(lower)alkylamino by N-alkylation of the corresponding compounds offormula I in which R⁷ is hydrogen, is considered to be a process whichwould be functionally equivalent to the process embodied herein for thepreparation of these compounds.

It will also be apparent to those skilled in the art that the processestaught herein for the preparation of the indole derivatives of formula Iare applicable likewise to the preparation of the indole derivatives offormula Ia, described above. In the latter case, the appropriatestarting material of formula IIa, see below, prepared analogously to thestarting material of formula II, is utilized.

More specifically, the acid and ester compounds of formula Ia in whichR^(6a), R^(6b), R^(6c), R^(6d) and R⁷ are as defined in the firstinstance, Z is hydroxy or lower alkoxy, and R¹, R², R³, R⁴, R⁵, X and Yare as defined in the first instance, are readily prepared by thecondensation (IIa + VI→VIIa), illustrated below, according to theconditions described previously for the condensation (II + VI→VII).##STR13## in which R¹, R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c), R^(6d),R⁷, X, Y and R¹⁶ are as defined in the first instance.

Likewise, the acid compounds of formula Ia in which R^(6a), R^(6b),R^(6c), R^(6d) are as defined in the first instance, Z is hydroxy andR¹, R², R³, R⁴, R⁵, R⁷, X and Y are as defined in the first instance maybe prepared by the following process: ##STR14## in which R¹, R², R³, R⁴,R⁵, X, Y, Y', R^(6a), R^(6b), R^(6c), R^(6d), R⁷, and R¹⁷ are as definedin the first instance according to the process disclosed above for theconversion {II + VIII→ IX→ X→XI→I (Z = OH)}. Subsequent transformationof the above acid and ester compounds of formula Ia to theircorresponding N-alkylated and amide derivatives of formula Ia iseffected in the same manner for the similar conversions of the acidester compounds of formula I, described herein.

Alternatively, the amide derivatives of formula Ia are prepared by thecondensation of an appropriate starting material of formula IIa with anappropriate α-, β-, γ- or δ-ketoamide in the presence of a suitable acidcatalyst according to the conditions described previously for thecondensation (II + VI→VII).

The following examples will illustrate further this invention.

EXAMPLE 1 1-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]indole-1-Acetic Acid(I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O, Y = CH₂ CO and Z =OH)

Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of thestarting material of formula II, tryptophol (10.0 g., 0.06 moles). in200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonicacid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate(Molecular Sieves No. 4) are added. The mixture is subjected to refluxfor thirty minutes, 600 mg. more of p-toluenesulfonic acid is added andrefluxing continued for 21/2 hours. The molecular sieves are collectedand the benzene solution washed successively with 5% sodium bicarbonateand water, dried over sodium sulfate, and evaporated under reducedpressure to dryneass affording an oil. The oil is subjected tochromatography on silica gel. Elution with 5% ether in benzene yieldsthe ester, 1-methyl-1,3,4,9-tetrahydropyrano-[ 3,4-b]indole-1-aceticacid ethyl ester, as an oil, γ_(max).sup. CHCl.sbsp.3 1715 cm⁻ ¹.

Hydrolysis of this ester to the title compound is effected as follows:The ester is dissolved in 230 ml. of methanol. To this is added 10 g. ofKOH in 30 ml. of H₂ O and the solution is allowed to stand at roomtemperature overnight. The methanol is evaporated, water added and thesolution washed with benzene. The aqueous phase is acidified with 6NHCl, and extracted with benzene. This organic phase is washed withwater, dried over sodium sulfate and evaporated to dryness to give anoil, which is crystallized from benzene containing a trace of petroleumether to afford the title compound, m.p. 150°-152° C., γ_(max)^(CHCl).sbsp.3 3325 and 1705 cm⁻ ¹.

An equivalent amount of methyl acetoacetate may replace ethylacetoacetate in the procedure of this Example. In this case,1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-acetic acid methyl ester,m.p. 87°-90° C. after recrystallization from benzenehexane, is obtainedas the ester.

An equivalent amount of propyl acetoacetate may replace ethylacetoacetate in the procedure of this Example. In this case,1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid propylester is obtained as the ester.

EXAMPLE 2 1-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]indole-1-PropionicAcid (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O, Y = CH₂ CH₂ COand Z = OH)

A mixture of the starting material of formula II, tryptophol (500 mg.),levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphoruspentoxide and about 0.5 g. of diatomaceous earth (Celite) is stirredmagnetically at room temperature for 15 minutes and then at 70° C. for11/2 hr. The reaction mixture is filtered. The filtrate is washed threetimes with 5N NaOH; the combined aqueous phase is washed twice withether and then rendered acidic with cold 50% HCl. The aqueous phase isextracted with chloroform. The chloroform extract is dried (Na₂ SO₄) andevaporated to dryness. The residue is crystallized from ethylacetate-petroleum ether to afford the title compound, m.p. 104°-110° C.,nmr (CDCl₃) δ 1.47 (3H), 2.18 (4H), 2.74 (2H), 3.96 (2H), 7.18 (4H),7.85 (1H), 9.60 (1.H).

The above title compound is also obtained by following the procedure ofExample 1 but replacing ethyl acetoacetate with an equivalent amount ofethyl levulinate. In this case 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid ethyl ester, m.p. 116°-118° C., γ_(max)^(CHCl).sbsp.3 1716 cm⁻ ¹, after crystallization from benzene-petroleumether, is obtained as the ester prior to hydrolysis.

EXAMPLE 3 1-Methyl-1,3,4,9-Tetrahydrothiopyrano[3,4-b]indole-1-AceticAcid (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = S, Y = CH₂ CO andZ = OH)

Indole-3-ethanethiol (1.5 g.) and methyl acetoacetate are mixed with 50ml. of benzene and the solution heated for 30 min. (bath temperature70°-80° C.). p-Toluenesulfonic acid (0.15 g.) is added and the reactionmixture is subjected to reflux and stirring for 12 hours. Water formedin the reaction mixture during this period is collected by a waterseparator. After cooling the benzene solution is washed with a 10%solution of sodium bicarbonate, water, saturated brine and dried oversodium sulfate. Evaporation of the benzene solution yields the ester,1-methyl-1, 3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methylester as a semi-solid, γ_(max) ^(CHCl).sbsp.3 1715 cm⁻ ¹.

This ester is then treated with aqueous alcoholic KOH in the mannerdescribed for the esters in Example 1 and 2 to afford the titlecompound, m.p. 147°-149° C., nmr (CDCl₃) δ1.86 (S, 3H), 3.06 and 8.12(6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H), afterrecrystallization from benzene-hexane.

The procedures of Examples 1, or 3 may be followed to prepare othercompounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶, X and Y are asdefined in the first instance, R⁷ is hydrogen and Z is hydroxy. Examplesof such compounds of formula I are listed Tables I and II. In each ofthese examples an equivalent amount of the starting material of formulaII listed therein is used instead of the starting material of formula IIdescribed in the procedures of Examples 1 and 3. Note that in each ofthese examples the ester obtained prior to hydrolysis is thecorresponding ester compound of formula I in which Z is a lower alkoxyof the product listed therein, the alkyl portion of said lower alkoxybeing derived from the R¹⁶ portion of the ketoester of formula VIemployed therein.

Similarly, the procedure of Example 2 may be used to prepare theproducts listed in Tables I and II. In this case an equivalent amount ofthe starting material of formula II, listed therein is used instead ofthe starting material of formula II described in Example 2 and anequivalent amount of the corresponding ketoacid of formula VI of theketoester of formula VI listed therein is used instead of the saidketoester.

                                      Table 1                                     __________________________________________________________________________     STARTING MATERIAL OF FORMULA II                                                                             ##STR15##                                                                                          ##STR16##                 __________________________________________________________________________    EX.                                                                              R.sup.2                                                                           R.sup.3                                                                          R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                             X R.sup.1 Y           R.sup.16                                                                         PREFIX//SUFFIX             __________________________________________________________________________    4  H   H  H    H    H     O CH.sub.3                                                                              CO          C.sub.2 H.sub.5                                                                  1-methyl//carboxylic                                                          acid                       5  CH.sub.3                                                                          H  H    H    H     O C.sub.2 H.sub.5                                                                       CO          C.sub.2 H.sub.5                                                                  1-ethyl-3-methyl//                                                            carboxylic acid            6  n-C.sub.3 H.sub.7                                                                 H  H    H    5-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                     CO          CH.sub.3                                                                         1,3-diisopropyl-6-                                                            methyl//carboxylic                                                            acid                       7  CH.sub.3                                                                          CH.sub.3                                                                         H    H    5-OH  O CH.sub.3 CHCH                                                                         CO          CH.sub.3                                                                         3,3-dimethyl-6-hydroxy                                                        4                                                                             1-(1-propenyl)//                                                              carboxylic acid            8  H   H  H    H    7-C.sub.2 H.sub.5                                                                   O HCC     CO          CH.sub.3                                                                         8-ethyl-1-ethynyl//                                                           carboxylic acid            9  H   H  2-C.sub.3 H.sub.7                                                                  H    H     O                                                                                ##STR17##                                                                            CO          CH.sub.3                                                                         1-cyclopropyl-4-isopro-                                                        pyl//carboxylic acid      10 CH.sub.3                                                                          CH.sub.3                                                                         C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    H     O                                                                                ##STR18##                                                                            CO          CH.sub.3                                                                         1-cyclopentyl-4,4-                                                            diethyl-3,3-dimethyl//                                                        arboxylic acid             11 H   H  H    H    H     O                                                                                ##STR19##                                                                            CO          CH.sub.3                                                                         1-phenyl//carboxylic                                                          acid                       12 CH.sub.3                                                                          C.sub.2 H.sub.5                                                                  H    H    H     O                                                                                ##STR20##                                                                            CO          CH.sub.3                                                                         1-benzyl-3-ethyl-                                                             3-methyl//carboxylic                                                          acid                       13 H   H  H    H    6-Cl  O                                                                                ##STR21##                                                                            CO             7-chloro-1-(2-                                                                thienyl)//carboxylic                                                          acid                       14 H   H  CH.sub.3                                                                           H    H     O CH.sub.3                                                                              CH.sub.2 CO C.sub.2 H.sub.5                                                                  1,4-dimethyl//acetic                                                          acid m.p.                                                                     163-164° C.         15 H   H  H    H    H     O C.sub.2 H.sub.5                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                  1-ethyl//acetic acid,                                                         m.p. 137-140°                                                          C.                         16 H   H  H    H    H     O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  1-propyl//acetic acid                                                         m.p. 148-151°       __________________________________________________________________________                                                       C.                          STARTING MATERIAL OF FORMULA II                                                                             KETOESTER OF FORMULA VI (R.sup.1COYOR.sup.1                                  6)                                                                                                  ##STR22##                 __________________________________________________________________________    EX.                                                                              R.sup.2                                                                           R.sup.3                                                                          R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                             X R.sup.1 Y           R.sup.16                                                                         PREFIX//SUFFIX             __________________________________________________________________________    17 H   H  H    H    H     O i-C.sub.3 H.sub.7                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  1-isopropyl//acetic                                                           acid, m.p.                                                                    150-152° C.         18 CH.sub.3                                                                          H  H    H    H     O CH.sub.2CHCH.sub.2                                                                    CH.sub.2 CO C.sub.2 H.sub.5                                                                  1-allyl-3-methyl//                                                            acetic acid                19 CH.sub.3                                                                          H  H    H    H     O n-C.sub.3 H.sub.5                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  3-methyl-1-propyl//                                                           acetic acid                                                                   m.p. 75-80° C.                                                         (Isomer A), m.p. 146-                                                         148° C (Isomer                                                         B).                        20 CH.sub.3                                                                          H  C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           H     O HCC     CH.sub.2 CO C.sub.2 H.sub.5                                                                  4-ethyl-1-ethynyl-3-                                                          methyl//acetic acid,                                                          ν.sub.max.sup.CHCl                                                         3  3300,2135,1710cm.sup                                                       .-                         21 H   H  H    H    H     O CH.sub.3                                                                              CH(CH).sub.3 CO                                                                           C.sub.2 H.sub.5                                                                  α,1-dimethyl//ace                                                       tic                                                                           acid; m.p.                                                                    154-156° C.                                                            (Isomer A), m.p. 163-                                                         165° C. (Isomer                                                        B).                        22 H   H  H    H    H     O                                                                                ##STR23##                                                                            C(CH.sub.3).sub.2 CO                                                                      C.sub.2 H.sub.5                                                                  1-cyclohexyl-α,.a                                                       lpha.- dimethyl//acetic                                                        acid                      23 H   H  H    H    H     O                                                                                ##STR24##                                                                            CH.sub.2 CO C.sub.2 H.sub.5                                                                  1-phenyl//acetic acid,                                                        .p. 148-150°                                                           C.                         24 H   H  H    H    H     O t-C.sub.4 H.sub.9                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  1-t-butyl//acetic                                                             acid,                                                                         m.p. 210-212°                                                          C.                         25 H   H  H    H    H     O n-C.sub.4 H.sub.9                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  1-butyl//acetic acid                                                          m.p. 124-127°                                                          C                          26 H   H  H    H    7-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  8-methyl-1-propyl//                                                           acetic acid m.p. 127-                                                         128° C              27 H   H  H    H    H     O                                                                                ##STR25##                                                                            CH.sub.2 CO C.sub.2 H.sub.5                                                                  1-(2-thienyl)//acetic                                                         acid m.p.                                                                     127-130° C.         28 H   H  H    H    5-Br  O C.sub.2 H.sub.5                                                                       CH.sub.2 CO C.sub.2 H.sub.5                                                                  6-bromo-1-ethyl//acetic                                                       acid m.p.                                                                     182-184° C.         29 H   H  H    H    5-OCH.sub.3                                                                         O CH.sub.3                                                                              CH.sub.2 CO CH.sub.3                                                                         6-methoxy-1-methyl//                                                          acetic acid, m.p.                                                             142-143° C.         30 H   H  H    H    5-OCOCH.sub.3                                                                       O CH.sub.3                                                                              CH.sub.2 CO C.sub.2 H.sub.5                                                                  6-acetoxy-1-methyl//                                                          acetic acid, m.p.                                                             142-143° C.         31 H   H  H    H    5-benzyl-                                                                           O CH.sub.3                                                                              CH.sub.2 CO C.sub.2 H.sub.5                                                                  6-benzyloxy-1-methyl//                         oxy                            acetic acid, m.p.                                                             163.5° C.           32 H   H  H    H    4-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  5-methyl-1-propyl//                                                           acetic acid, m.p.                                                             177-178° C.         33 H   H  H    H    6-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  7-methyl-1-propyl//                                                           acetic acid, m.p.                                                             157-158° C.         34 H   H  H    H    5-NO.sub.2                                                                          O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  6-nitro-1-propyl//                                                            acetic acid, m.p.                                                             119-                                                                          120° C.             35 i-C.sub.3 H.sub.7                                                                 H  i-C.sub.3 H.sub.7                                                                  H    5-NO.sub.2                                                                          O CH.sub.2CH                                                                            CH(CH.sub.3)CO                                                                            C.sub.2 H.sub.5                                                                  3,4-diisopropyl-α                                                       -                                                                             methyl-6-nitro-1-                                                             vinyl//acetic acid         36 H   H  CH.sub.3                                                                           CH.sub.3                                                                           H     O n-C.sub.3 H.sub.7                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                  4,4-dimethyl-1-                                                               propyl//acetic acid,                                                          m.p. 184-185°                                                          C.                         37 H   H  C.sub.2 H.sub.5                                                                    H    7-CH.sub.3                                                                          O HCC     C(i-C.sub.3 H.sub.7).sub.2 CO                                                             C.sub.2 H.sub.5                                                                  α,α-diisopr                                                       opyl-4- ethyl-1-ethynyl                                                       -8- methyl//acetic                                                            acid                       38 CH.sub.3                                                                          CH.sub.3                                                                         H    H    5-OC.sub.2 H.sub.5                                                                  O                                                                                ##STR26##                                                                            CH(C.sub.2 H.sub.5)CO                                                                     C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,.                                                       alpha.- diethyl-3,3-dim                                                       ethyl- 6-ethoxy//acetic                                                        acid                      39 CH.sub.3                                                                          CH.sub.3                                                                         C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    6-C.sub.2 H.sub.5                                                                   O                                                                                ##STR27##                                                                            C(CH.sub.3).sub.2 CO                                                                      C.sub.2 H.sub.5                                                                  1-cyclohexyl-α,.a                                                       lpha.,3,3- tetramethyl-                                                       4,4,7- triethyl//acetic                                                        acid                      40 CH.sub.3                                                                          H  n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  4-n-C.sub.3 H.sub.7                                                                 O                                                                                ##STR28##                                                                            CH(CH.sub.3)CO                                                                            C.sub.2 H.sub.5                                                                  α,3-dimethyl-1-ph                                                       enyl 4,4,5-tripropyl//                                                        cetic acid                 41 H   H  H    H    H     O                                                                                ##STR29##                                                                            C(CH.sub.3).sub.2 CO                                                                      C.sub.2 H.sub.5                                                                  α,α-dimethy                                                       l-1-phenyl acetic                                                             acid                       42 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    4-C.sub.2 H.sub.5                                                                   O                                                                                ##STR30##                                                                            C(i-C.sub.3 H.sub.7).sub.2 CO                                                             C.sub.2 H.sub.5                                                                  1-benzyl-α,.alpha                                                       .- diisopropyl-3,3,4,4,                                                       5 pentaethyl//acetic                                                          acid                       43 CH.sub.3                                                                          H  H    H                                                                                   ##STR31##                                                                          O                                                                                ##STR32##                                                                            C(CH.sub.3).sub.2 CO                                                                      C.sub.2 H.sub.5                                                                  1-benzyl-8-propionoxy                                                         α,α,3-trime                                                       thyl// acetic acid         44 H   H  CH.sub.3                                                                           H    H     O                                                                                ##STR33##                                                                            CH(CH.sub.3)CO                                                                            C.sub.2 H.sub.5                                                                  α,4-dimethyl-1-                                                         2-thienyl)//acetic                                                            acid                       45 H   H  H    H    H     O                                                                                ##STR34##                                                                            C(CH.sub.3).sub.2 CO                                                                      C.sub.2 H.sub.5                                                                  α,α-dimethy                                                       l-1- (2-thienyl)//aceti                                                       c acid                     46 H   H  H    H    4-I   O i-C.sub.3 H.sub.7                                                                     CH.sub.2 CH.sub.2 CO                                                                      C.sub.2 H.sub.5                                                                  5-iodo-1-isopropyl//                                                          propionic acid             47 CH.sub.3                                                                          CH.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                                                            ##STR35##                                                                          O CH.sub.2CH                                                                            CH.sub.2 CH(CH.sub.3)CO                                                                   C.sub.2 H.sub.5                                                                  8-acetoxy-α,3,3,4                                                       ,4- pentamethyl-1-vinyl                                                       // propionic acid          48 H   H  H    H    6-OH  O HCCCH.sub.2                                                                           C(C.sub.2 H.sub.5).sub.2 CH.sub.2 -                                           CO          C.sub.2 H.sub.5                                                                  β,β-diethyl-7                                                       -hydroxy 1-(2-propynyl)                                                       // propionic acid          49 CH.sub.3                                                                          H  H    H    7-NO.sub.2                                                                          O                                                                                ##STR36##                                                                            CH.sub.2 CH(n-C.sub.3 H.sub.7)-                                                           C.sub.2 H.sub.5                                                                  1-cyclobutyl-3-methyl                                                         8-nitro-α-propyl/                                                       / propionic acid           50 H   H  CH.sub.3                                                                           H    5-CH.sub.3                                                                          O                                                                                ##STR37##                                                                            C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                           CO          C.sub.2 H.sub.5                                                                  α,α,β,                                                       β,4,6-hexamethyl                                                         1-phenyl//propionic                                                           acid                       51 i-C.sub.3 H.sub.7                                                                 H  H    H    7-Br  O                                                                                ##STR38##                                                                            CH(CH.sub.3)CH(C.sub.2 H.sub.5)CO                                                         C.sub.2 H.sub.5                                                                  1-benzyl-8-bromo-.alpha                                                       .- ethyl-3-isopropyl-.b                                                       eta.- methyl//propionic                                                        acid                      52 C.sub.2 H.sub.5                                                                   H  C.sub.2 H.sub.5                                                                    H    7-Cl  O                                                                                ##STR39##                                                                            CH.sub.2 CH.sub.2 CH.sub.2 CO                                                             C.sub.2 H.sub.5                                                                  8-chloro-3,4-diethyl-                                                         1-(2-thienyl)//                                                               propionic acid             53 CH.sub.3                                                                          H  H    H    H     O CH.sub.3                                                                              CH.sub.2 C(n-C.sub.3 H.sub.7).sub.2                                           CO          C.sub.2 H.sub.5                                                                  1,3-dimethyl-α,.a                                                       lpha.-                                                                        dipropyl//propionic                                                           acid                       54 CH.sub.3                                                                          H  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    H     O                                                                                ##STR40##                                                                            CH(CH.sub.3)C(CH.sub.3).sub.2                                                             CH.sub.3                                                                         4,4-diethyl-1-                                                                methallyl-α,.alph                                                       a.,β,3- tetramethy                                                       l// propionic acid         55 H   H  CH.sub.3                                                                           CH.sub.3                                                                           H     O HCC     C(CH.sub.3).sub.2 CH.sub.2 CO                                                             CH.sub.3                                                                         1-ethynyl-β,β                                                       ,4,4- tetramethyl//prop                                                       ionic acid                 56 H   H  n-C.sub.3 H.sub.7                                                                  H                                                                                   ##STR41##                                                                          O                                                                                ##STR42##                                                                            C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                            H.sub.5)CO  CH.sub.3                                                                         1-cyclopentyl-5-                                                              propionoxy-4-propyl-                                                          α,β,β-t                                                       riethyl// propionic                                                           acid                       57 n-C.sub.3 H.sub.7                                                                 H  H    H    4-OCH.sub.3                                                                         O                                                                                ##STR43##                                                                            CH.sub.2 CH(CH.sub.3)CO                                                                   C.sub.2 H.sub.5                                                                  5-methoxy-α-methy                                                       l- 1-phenyl-3-propyl//                                                        ropionic acid              58 H   H  i-C.sub.3 H.sub.7                                                                  H    6-benzyl- oxy                                                                       O                                                                                ##STR44##                                                                            CH.sub.2 CH(C.sub.2 H.sub.5)CO                                                            C.sub.2 H.sub.5                                                                  1-benzyl-7-benzyloxy-                                                         α-ethyl-4-isoprop                                                       yl// propionic acid        59 CH.sub.3                                                                          CH.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                                                           7-Cl  O                                                                                ##STR45##                                                                            CH(CH.sub.3)CH.sub.2 CO                                                                   C.sub.2 H.sub.5                                                                  8-chloro-8,3,3,4,4-                                                           pentamethyl-1-                                                                (2-thienyl)//propionic                                                        cid                        60 C.sub.2 H.sub.5                                                                   H  H    H    5-NO.sub.2                                                                          O CH.sub.3                                                                              CH(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                           H.sub.5).sub.2 CO                                                                         C.sub.2 H.sub.5                                                                  1-methyl-6-nitro-.alpha                                                       .,α-                                                                    β,β,3-pentaet                                                       hyl//                                                                         propionic acid             61 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  H    H    5-F   O CH.sub.2CHCH.sub.2                                                                    CH(C.sub.2 H.sub.5)CH(CH.sub.3)CO                                                         C.sub.2 H.sub.5                                                                  1-allyl-6-fluoro-.alpha                                                       .-                                                                            methyl-β,3,3-triet                                                       hyl//                                                                         propionic acid             62 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  H    H    4-C.sub.2 H.sub.5                                                                   O CH.sub.3 CCH                                                                          C(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                           CH.sub.3                                                                         β-propyl-1-(1-                                                           propynyl)-3,3,5-                                                              triethyl//propionic                                                           acid                       63 H   H  H    H    6-OC.sub.2 H.sub.5                                                                  O                                                                                ##STR46##                                                                            CH(C.sub.2 H.sub.5)CH(C.sub.2                                                 H.sub.5)CO  C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,.                                                       beta.- diethyl-6-ethoxy                                                       // propionic acid          64 CH.sub.3                                                                          CH.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                                                           6-O-n-C.sub.3 H.sub.7                                                               O                                                                                ##STR47##                                                                            C(CH.sub.3).sub.2 CH(CH.sub.3)CO                                                          C.sub.2 H.sub.5                                                                  α,β,β,3                                                       ,3,4,4- heptamethyl-1-p                                                       henyl- 7-propoxy//propi                                                       onic acid                  65 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  H    H    5-CH.sub.3                                                                          O                                                                                ##STR48##                                                                            C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                           CO          C.sub.2 H.sub.5                                                                  1-benzyl-3,3-diethyl-                                                         α,α,β,                                                       β,6-pentamethyl//                                                        ropionic acid              66 n-C.sub.3 H.sub.7                                                                 H  H    H    4-OH  O                                                                                ##STR49##                                                                            C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                           CO          C.sub.2 H.sub.5                                                                  5-hydroxy-3-propyl-                                                           α,α,β,                                                       β-tetramethyl-                                                           1-(2-thienyl)//                                                               propionic acid             67 H   H  H    H    H     O CH.sub.3                                                                              CH.sub.2 CH.sub.2 CH.sub.2 CO                                                             C.sub.2 H.sub.5                                                                  1-methyl//butyric                                                             acid, m.p.                                                                    132-135° C          68 CH.sub.3                                                                          H  H    H    H     O C.sub.2 H.sub.5                                                                       CH(CH.sub.3)CH.sub.2 CH.sub.2                                                             C.sub.2 H.sub.5                                                                  γ,3-dimethyl-1-et                                                       hyl//                                                                         butyric acid               69 CH.sub.3                                                                          CH.sub.3                                                                         H    H    H     O n-C.sub.3 H.sub.7                                                                     C(C.sub.2 H.sub.5).sub.2 CH.sub.2                                             CH.sub.2 CO C.sub.2 H.sub.5                                                                  γ,γ-diethyl                                                       -3,3-                                                                         dimethyl-1-propyl//                                                           butyric acid               70 CH.sub.3                                                                          CH.sub.3                                                                         n-C.sub.3 H.sub.7                                                                  H    H     O CH.sub.2CH                                                                            O(n-C.sub.3 H.sub.7).sub.2 CH(n-C.sub.                                        3 H.sub.7)CH.sub.2 CO                                                                     C.sub.2 H.sub.5                                                                  3,3-dimethyl-β,.ga                                                       mma.,γ,4-                                                               tetrapropyl-1-vinyl//                                                         butyric acid               71 H   H  H    H    H     O CH.sub.2CHCH.sub.2                                                                    [C(CH.sub.3).sub.2]2 CH.sub.2                                                             C.sub.2 H.sub.5                                                                  1-allyl-β,β,.                                                       gamma.,γ-                                                               tetramethyl//butyric                                                          acid                       72 H   H  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    6-Cl  O CH.sub.2CH                                                                            [C(C.sub.2 H.sub.5).sub.2]2 CH(C.sub.2                                         H.sub.5)CO C.sub.2 H.sub.5                                                                  7-chloro-α,β                                                       ,β,γ,γ                                                       ,4-                                                                           4-heptaethyl-1-vinyl//                                                        butyric acid               73 H   H  CH.sub.3                                                                           H    4-CH.sub.3                                                                          O HCCH    [C(CH.sub.3).sub.2]3 CO                                                                   C.sub.2 H.sub.5                                                                  1-ethynyl-α,.alph                                                       a.,β,β,.gamma                                                       .,γ, 4,5-octameth                                                       yl// butyric acid          74 C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                    H    5-O OCCH.sub. 3                                                                     O                                                                                ##STR50##                                                                            CH(C.sub.2 H.sub.5)[C(C.sub.2                                                 H.sub.5)].sub.2 CO                                                                        C.sub.2 H.sub.5                                                                  6-acetoxy-α,.alph                                                       a.,β,β,.gamma                                                       .,3, 3,4-octaethyl-1-                                                         (1-propynyl)//butyric                                                         acid                       75 H   H  CH.sub.3                                                                           CH.sub.3                                                                           7-OCH.sub.3                                                                         O                                                                                ##STR51##                                                                            CH.sub.2 [C(CH.sub.3).sub.2]2                                                             C.sub.2 H.sub.5                                                                  1-cyclobutyl-α,.a                                                       lpha.,β,β-                                                          4,4-hexamethyl-8-                                                             methoxy//butyric acid      76 H   H  H    H    4-Br  O                                                                                ##STR52##                                                                            CH.sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2                                         CO         C.sub.2 H.sub.5                                                                  5-bromo-1-cyclopentyl-                                                        α,α,β-                                                       trimethyl// butyric                                                           acid                       77 CH.sub.3                                                                          CH.sub.3                                                                         H    H    4-n-C.sub.3 H.sub.7                                                                 O                                                                                ##STR53##                                                                            CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).s                                        ub.2 CO     C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,.                                                       alpha.- diethyl-3,3-dim                                                       ethyl- 5-propyl//butyri                                                       c acid                     78 H   H  H    H    7-C.sub.2 H.sub.5                                                                   O                                                                                ##STR54##                                                                            CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                          C.sub.2 H.sub.5                                                                  8-ethyl-α-methyl-                                                       1- phenyl//butyric                                                            acid                       79 CH.sub.3                                                                          CH.sub.3                                                                         CH.sub.3                                                                           H    5-F   O                                                                                ##STR55##                                                                            [CH(CH.sub.3)].sub.3 CO                                                                   C.sub.2 H.sub.5                                                                  6-fluoro-α,β                                                       ,γ,3,3,4-                                                               hexamethyl-1-phenyl//                                                         butyric acid               80 CH.sub.3                                                                          CH.sub.3                                                                         H    H    4-CH.sub.3                                                                          O                                                                                ##STR56##                                                                            CH(C.sub.2 H.sub.5)CH.sub.2 CH(C.sub.2                                         H.sub.5)CO C.sub.2 H.sub.5                                                                  α,γ-diethyl                                                       -1-phenyl- 3,3,5-trimet                                                       hyl// butyric acid         81 C.sub.2 H.sub.5                                                                   H  H    H    6-NO.sub.2                                                                          O                                                                                ##STR57##                                                                            [CH(CH.sub.3)].sub.3 CO                                                                   C.sub.2 H.sub.5                                                                  1-benzyl-3-ethyl-2-                                                           nitro-α,β,.g                                                       amma.- trimethyl//butyr                                                       ic acid                    82 CH.sub.3                                                                          CH.sub.3                                                                         H    H    4-n-C.sub.3 H.sub.7                                                                 O                                                                                ##STR58##                                                                            CH.sub.2 [CH(C.sub.2 H.sub.5)].sub.2                                          CO          C.sub.2 H.sub.5                                                                  1-benzyl-α,β                                                       -diethyl- 3,3-dimethyl-                                                       5- propyl//butyric                                                            acid                       83 H   H  H    H    7-CH  O                                                                                ##STR59##                                                                            C(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3)                                        .sub.2 CO   C.sub.2 H.sub.5                                                                  1-benzyl-8-hydroxy-                                                           α,α,γ                                                       ,γ-tetramethyl//                                                        utyric acid                84 CH.sub.3                                                                          H  CH.sub.3                                                                           H    4-OC.sub.2 H.sub.5                                                                  O                                                                                ##STR60##                                                                            [C(CH.sub.3).sub.2]3 CO                                                                   C.sub.2 H.sub.5                                                                  5-ethoxy-α,.alpha                                                       .,β,β,γ                                                       ,γ, 3,4-octomethy                                                       l-1- (2-thienyl)//                                                            butyric acid               85 C.sub.2 H.sub.5                                                                   H  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    6-Cl  O                                                                                ##STR61##                                                                            CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).s                                        ub.2 CO     C.sub.2 H.sub.5                                                                  7-chloro-α,.alpha                                                       .,3,4,4- pentaethyl-1-                                                        2-thienyl)// butyric                                                          acid                       86 CH.sub.3                                                                          CH.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                                                           4-Br  O                                                                                ##STR62##                                                                            CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                          C.sub.2 H.sub.5                                                                  5-bromo-α,3,3,4,4                                                       - pentamethyl-1-                                                              (2-thienyl)// butyric                                                         acid                       __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________     EX.                                                                              ##STR63##                                                                                             ##STR64##                                                                                           ##STR65##                   __________________________________________________________________________       R.sup.2                                                                            R.sup.3                                                                          R.sup.4                                                                           R.sup.5                                                                          R.sup.6                                                                              X R.sup.1   Y        R.sup.16                                                                         PREFIX//SUFFIX               __________________________________________________________________________    87 H    H  H   H  H      S CH.sub.3  CO       C.sub.2 H.sub.5                                                                  1-methyl//carboxylic                                                          acid                         88 CH.sub.3                                                                           H  H   H  H      S C.sub.2 H.sub.5                                                                         CO       C.sub.2 H.sub.5                                                                  1-ethyl-3-methyl//                                                            carboxylic acid              89 i-C.sub.3 H.sub.7                                                                  H  H   H  5-CH.sub.3                                                                           S i-C.sub.3 H.sub.7                                                                       CO       CH.sub.3                                                                         1,3-diisopropyl-6-                                                            methyl//carboxylic                                                            acid                         90 CH.sub.3                                                                           CH.sub.3                                                                         H   H  5-OH   S CH.sub.3 CHCH                                                                           CO       CH.sub.3                                                                         3,3-dimethyl-6-                                                               hydroxy-1-1-propenyl)/                                                        carboxylic acid              91 H    H  H   H  7-C.sub.2 H.sub.5                                                                    S                                                                                ##STR66##                                                                              CO       CH.sub.3                                                                         8-ethyl-1-ethynyl//                                                           carboxylic acid              92 H    H  i-C.sub.3 H.sub.7                                                                 H  H      S                                                                                ##STR67##                                                                              CO       CH.sub.3                                                                         1-cyclopropyl-4-iso-                                                          propyl//carboxylic acid      93 CH.sub.3                                                                           CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  H      S                                                                                ##STR68##                                                                              CO       CH.sub.3                                                                         1-cyclopentyl-4,4-                                                            diethyl-3,3-dimethyl//                                                        carboxylic acid              94 H    H  H   H  H      S                                                                                ##STR69##                                                                              CO       CH.sub.3                                                                         1-phenyl//carboxylic                                                          acid                         95 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                  H   H  H      S                                                                                ##STR70##                                                                              CO       CH.sub.3                                                                         1-benzyl-3-ethyl-                                                             3-methyl//carboxylic                                                          acid                         96 H    H  H   H  6-Cl   S                                                                                ##STR71##                                                                              CO          7-chloro-1-(2-thienyl)//                                                      arboxylic acid               97 H    H  CH.sub.3                                                                          H  H      S CH.sub.3  CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  1,4-dimethyl//acetic                                                          acid                         98 H    H  H   H  H      S C.sub.2 H.sub.5                                                                         CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  1-ethyl//acetic acid,                                                         m.p. 138° C.          99 H    H  H   H  H      S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  1-propyl//acetic acid,                                                        m.p. 127-129° C.      100                                                                              H    H  H   H  H      S i-C.sub.3 H.sub.7                                                                       CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  1-isopropyl//acetic                                                           acid                         101                                                                              CH.sub.3                                                                           H  H   H  H      S CH.sub.2CHCH.sub.2                                                                      CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  1-allyl-3-methyl//                                                            acetic acid                  102                                                                              CH.sub.3                                                                           H  H   H  H      S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  3-methyl-1-propyl//                                                           acetic acid                  103                                                                              CH.sub.3                                                                           H  C.sub.2 H.sub.5                                                                   CH.sub.3                                                                         H      S                                                                                ##STR72##                                                                              CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  4-ethyl-1-ethynyl-                                                            3-methyl//acetic acid        104                                                                              H    H  H   H  H      S CH.sub.3  CH(CH.sub.3)CO                                                                         C.sub.2 H.sub.5                                                                  α,1-dimethyl//aceti                                                     c                                                                             acid                         105                                                                              H    H  H   H  H      S                                                                                ##STR73##                                                                              C(CH.sub.3).sub.2 CO                                                                   C.sub.2 H.sub.5                                                                  1-cyclohexyl-α,.alp                                                     ha.- dimethyl//acetic                                                         acid                         106                                                                              H    H  H   H  H      S                                                                                ##STR74##                                                                              CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  1-phenyl//acetic acid        107                                                                              H    H  H   H  H      S t-C.sub.4 H.sub.9                                                                       CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  1-5-butyl//acetic                                                             acid                         108                                                                              H    H  H   H  H      S n-C.sub.4 H.sub.9                                                                       CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  1-butyl//acetic acid         109                                                                              H    H  H   H  7-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  8-methyl-1-propyl//                                                           acetic acid                  110                                                                              H    H  H   H  H      S                                                                                ##STR75##                                                                              CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  1-(2-thienyl)// acetic                                                        acid                         111                                                                              H    H  H   H  5-Br   S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  6-bromo-1-propyl//                                                            acetic acid                  112                                                                              H    H  H   H  5-OCH.sub.3                                                                          S CH.sub.3  CH.sub.2 CO                                                                            CH.sub.3                                                                         6-methoxy-1-methyl//                                                          acetic acid                                                                   PRODUCT: [(PREFIX                                                             LISTED BELOW)-1,3,4,9-                                                        TETRAHYDROTHIOPYRANO-           STARTING MATERIAL OF    KETOESTER OF FORMULA VI                                                                             [3,4-b]INDOLE-1-             EX.                                                                              FORMULA II              (R.sup.1COYOR.sup.16) (SUFFIX LISTED               __________________________________________________________________________                                                     BELOW)                          R.sup.2                                                                            R.sup.3                                                                          R.sup.4                                                                           R.sup.5                                                                          R.sup.6                                                                              X R.sup.1   Y        R.sup.16                                                                         PREFIX//SUFFIX               __________________________________________________________________________    113                                                                              H    H  H   H  5-OCOCH.sub.3                                                                        S CH.sub.3  CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  6-acetoxy-1-methyl//                                                          acetic acid                  114                                                                              H    H  H   H  5-benzyl-                                                                            S CH.sub.3  CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  6-benzyloxy-1-                                 oxy                            methyl//acetic acid          115                                                                              H    H  H   H  4-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO                                                                            C.sub.2 H.sub.5                                                                  5-methyl-propyl//                                                             acetic acid                  116                                                                              H    H  H   H  6-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                       CH.sub.2 CO                                                                            C.sub.2 H.sub.7                                                                  7-methyl-1-propyl//                                                           acetic acid                  117                                                                              H    H  H   H  7-F    S CH.sub.2CH                                                                              C(C.sub.2 H.sub.5).sub.2 CO                                                            C.sub.2 H.sub.5                                                                  α,α-diethyl-8                                                     -                                                                             fluoro-1-vinyl//                                                              acetic acid                  118                                                                              i-C.sub.3 H.sub.7                                                                  H  i-C.sub.3 H.sub.7                                                                 H  5-NO.sub.2                                                                           S CH.sub.2CH                                                                              CH(CH.sub.3)CO                                                                         C.sub.2 H.sub.5                                                                  3,4-diisopropyl-α-                                                      O                                                                             methyl-6-nitro-                                                               1-vinyl//acetic                                                               acid                         119                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H   H  5-Cl   S                                                                                ##STR76##                                                                              CH(i-C.sub.3 H.sub.7)CO                                                                C.sub.2 H.sub.5                                                                  6-chloro-3,3-dimethyl                                                         α-isopropyl-1-                                                          (1-propynyl)//acetic                                                          acid                         120                                                                              H    H  C.sub.2 H.sub.5                                                                   H  7-CH.sub.3                                                                           S                                                                                ##STR77##                                                                              C(i-C.sub.3 H.sub.7).sub.2 CO                                                          C.sub.2 H.sub.5                                                                  α,α-diisoprop                                                     yl- 4-ethyl-1-ethynyl-                                                        8-methyl//acetic acid        121                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H   H  5-OC.sub.2 H.sub.5                                                                   S                                                                                ##STR78##                                                                              CH(C.sub.2 H.sub.5)CO                                                                  C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,.al                                                     pha.- diethyl-3,3-                                                            dimethyl-6-ethoxy//                                                           acetic acid                  122                                                                              CH.sub.3                                                                           CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  6-C.sub.2 H.sub.5                                                                    S                                                                                ##STR79##                                                                              C(CH.sub.3).sub.2 CO                                                                   C.sub.2 H.sub.5                                                                  1-cyclohexyl-α,.alp                                                     ha.,3,3- tetramethyl-4,4,                                                     7- triethyl//acetic                                                           acid                         123                                                                              CH.sub.3                                                                           H  n-C.sub.3 H.sub.7                                                                 n-C.sub.3 H.sub.7                                                                4-n-C.sub.3 H.sub.7                                                                  S                                                                                ##STR80##                                                                              CH(CH.sub.3)CO                                                                         C.sub.2 H.sub.5                                                                  α,3-dimethyl-1-phen                                                     yl 4,4,5-tripropyl//                                                          acetic acid                  124                                                                              H    H  H   H  H      S                                                                                ##STR81##                                                                              C(CH.sub.3).sub.2 CO                                                                   C.sub.2 H.sub.5                                                                  α,α-dimethyl-                                                     1-phenyl acetic acid         125                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  4-C.sub.2 H.sub.5                                                                    S                                                                                ##STR82##                                                                              C(i-C.sub.3 H.sub.7).sub.2 CO                                                          C.sub.2 H.sub.5                                                                  1-benzyl-α,α-                                                      diisopropyl-3,3,4,4,5-                                                       pentaethyl//acetic acid      126                                                                              CH.sub.3                                                                           H  H   H                                                                                 ##STR83##                                                                           S                                                                                ##STR84##                                                                              C(CH.sub.3).sub.2 CO                                                                   C.sub.2 H.sub.5                                                                  1-benzyl-8-propionoxy-                                                        α,α,3-trimeth                                                     yl// acetic acid             127                                                                              H    H  CH.sub.3                                                                          H  H      S                                                                                ##STR85##                                                                              CH(CH.sub.3)CO                                                                         C.sub.2 H.sub.5                                                                  α,4-dimethyl-1-                                                         (2-thienyl)//acetic                                                           acid                         128                                                                              H    H  H   H  H      S                                                                                ##STR86##                                                                              C(CH.sub.3).sub.2 CO                                                                   C.sub.2 H.sub.5                                                                  α,α-dimethyl-                                                     1- (2-thienyl)//acetic                                                        acid                         129                                                                              H    H  H   H  H      S CH.sub.3  CH.sub.2 CH.sub.2 CO                                                                   C.sub.2 H.sub.5                                                                  1-methyl//                                                                    propionic acid               130                                                                              CH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                          CH.sub.3                                                                          ##STR87##                                                                           S CH.sub.2CH                                                                              CH.sub.2 CH(CH.sub.3)CO                                                                C.sub.2 H.sub.5                                                                  8-acetoxy-α,3,3,4,4                                                     - pentamethyl-1-vinyl//                                                       propionic                    131                                                                              H    H  H   H  6-OH   S                                                                                ##STR88##                                                                              CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                                      C.sub.2 H.sub.5                                                                  β,β-diethyl-7-h                                                     ydroxy- 1-(2-propynyl)//                                                      ropionic acid                132                                                                              CH.sub.3                                                                           H  H   H  7-NO.sub.2                                                                           S                                                                                ##STR89##                                                                              CH(n-C.sub.3 H.sub.7)- CH.sub.2                                                        C.sub.2 H.sub.5                                                                  1-cyclobutyl-3-methyl-                                                        8-nitro-α-propyl//                                                      ropionic acid                133                                                                              H    H  CH.sub.3                                                                          H  5-CH.sub.3                                                                           S                                                                                ##STR90##                                                                              C(CH.sub.3).sub.2 C- (CH.sub.3).sub.2                                          CO      C.sub.2 H.sub.5                                                                  α,α,β,.b                                                     eta.,4,6-hexamethyl-                                                          1-phenyl//propionic                                                           acid                         134                                                                              i-C.sub.3 H.sub.7                                                                  H  H   H  7-Br   S                                                                                ##STR91##                                                                              CH(CH.sub.3)CH- (C.sub.2 H.sub.5)CO                                                    C.sub.2 H.sub.5                                                                  1-benzyl-8-bromo-α                                                      thyl-3-isopropyl-β                                                       methyl//propionic acid       135                                                                              C.sub.2 H.sub.5                                                                    H  C.sub.2 H.sub.5                                                                   H  7-Cl   S                                                                                ##STR92##                                                                              CH.sub.2 CH.sub.2 CH.sub.2 CO                                                          C.sub.2 H.sub.5                                                                  8-chloro-3,4-diethyl-                                                         1-(2-thienyl)// propionic                                                      acid                        136                                                                              CH.sub.3                                                                           H  H   H  H      S CH.sub.3  CH.sub.2 C(n-C.sub.3 -                                                                 C.sub.2 H.sub.5                                                                  1,3-dimethyl-α,.alp                                                     ha.-                                                              H.sub.7).sub.2 CO                                                                         dipropyl//propionic                                                           acid                         137                                                                              CH.sub.3                                                                           H  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  H      S CH.sub.2C(CH.sub.3)CH.sub.2                                                             CH(CH.sub.3)C-                                                                         CH.sub.3                                                                         4,4-diethyl-1-                                                    (CH.sub.3).sub.2 CO                                                                       methalkyl-α,α                                                     ,β,3-                                                                    tetramethyl//                                                                 propionic acid               138                                                                              H    H  CH.sub.3                                                                          CH.sub.3                                                                         H      S                                                                                ##STR93##                                                                              C(CH.sub.3).sub.2 CH.sub.2 CO                                                          CH.sub.3                                                                         1-ethynyl-β,β,4                                                     ,4- tetramethyl//propioni                                                     c acid                       139                                                                              H    H  n-C.sub.3 H.sub.7                                                                 H                                                                                 ##STR94##                                                                           S                                                                                ##STR95##                                                                              C(C.sub.2 H.sub.5).sub.2 C- (C.sub.2                                          H.sub.5)CO                                                                             CH.sub.3                                                                         1-cyclopentyl-5-                                                              propionoxy-4-propyl-                                                          α,β,β-tri                                                     ethyl// propionic acid       140                                                                              n-C.sub.3 H.sub.7                                                                  H  H   H  4-OCH.sub.3                                                                          S                                                                                ##STR96##                                                                              CH.sub.2 CH(CH.sub.3)CO                                                                C.sub.2 H.sub.5                                                                  5-methoxy-α-methyl-                                                      1-phenyl-3-propyl//                                                          propionic acid               141                                                                              H    H  i-C.sub.3 H.sub.7                                                                 H  6-benzyl- oxy                                                                        S                                                                                ##STR97##                                                                              CH.sub.2 CH(C.sub.2 H.sub.5)CO                                                         C.sub.2 H.sub.5                                                                  1-benzyl-6-benzyloxy                                                          α-ethyl-4-isopropyl                                                     // propionic acid            142                                                                              CH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                          CH.sub.3                                                                         7-Cl   S                                                                                ##STR98##                                                                              CH(CH.sub.3)CH.sub.2 CO                                                                C.sub.2 H.sub.5                                                                  8-chloro-β,3,3,4,4-                                                      entamethyl-1- (2-thienyl)                                                     //propionic acid             143                                                                              C.sub.2 H.sub.5                                                                    H  H   H  5-NO.sub.2                                                                           S CH.sub.3  CH(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                           H.sub.5).sub.2 CO                                                                      C.sub.2 H.sub.5                                                                  1-methyl-6-nitro-α,                                                     α-                                                                      β,β,3-pentaethy                                                     l//                                                                           propionic acid               144                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                  H   H  5-F    S CH.sub.2CHCH.sub.2                                                                      CH(C.sub.2 H.sub.5)CH-                                                                 C.sub.2 H.sub.5                                                                  1-allyl-6-fluoro-α-                                         (CH.sub.3)CO                                                                              methyl-β,3,3-triethy                                                     l//                                                                           propionic acid               145                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                  H   H  4-C.sub.2 H.sub.5                                                                    S                                                                                ##STR99##                                                                              C(n-C.sub.3 H.sub.7)CH.sub.2                                                           CH.sub.3                                                                         β-propyl-1-(1-                                                           propynyl)-3,3,5-                                                              triethyl//propionic                                                           acid                         146                                                                              H    H  H   H  6-OC.sub.2 H.sub.5                                                                   S                                                                                ##STR100##                                                                             CH(C.sub.2 H.sub.5)CH- (C.sub.2                                               H.sub.5)CO                                                                             C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,.be                                                     ta.- diethyl-6-ethoxy//                                                       propionic acid               147                                                                              CH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                          CH.sub.3                                                                         6-O-n-C.sub.3 H.sub.5                                                                S                                                                                ##STR101##                                                                             C(CH.sub.3).sub.2 CH- (CH.sub.3)CO                                                     C.sub.2 H.sub.5                                                                  α,β,β,3,3                                                     ,4,4- heptamethyl-1-pheny                                                     l- 7-propoxy//propionic                                                       acid                         148                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                  H   H  5-CH.sub.3                                                                           S                                                                                ##STR102##                                                                             C(CH.sub.3).sub.2 C- (CH.sub.3).sub.2                                          CO      C.sub.2 H.sub.5                                                                  1-benzyl-3,3-diethyl-                                                         α,α,β,.b                                                     eta.,6-pentamethyl//                                                          propionic acid               149                                                                              n-C.sub.3 H.sub.7                                                                  H  H   H  4-OH   S                                                                                ##STR103##                                                                             C(CH.sub.3).sub.2 C- (CH.sub.3).sub.2                                          CO      C.sub.2 H.sub.5                                                                  5-hydroxy-3-propyl-                                                           α,α,β,.b                                                     eta.-tetramethyl-                                                             1-(2-thienyl)// propionic                                                      acid                        150                                                                              H    H  H   H  H      S CH.sub.3  CH.sub.2 CH.sub.2 CH.sub.2 CO                                                          C.sub.2 H.sub.5                                                                  1-methyl//butyric                                                             acid                         151                                                                              CH.sub.3                                                                           H  H   H  H      S C.sub.2 H.sub.5                                                                         CH(CH.sub.3)CH.sub.2                                                                   C.sub.2 H.sub.5                                                                  γ,3-dimethyl-1-ethy                                                     l//                                                               CH.sub.2 CO butyric acid                 152                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H   H  H      S n-C.sub.3 H.sub.7                                                                       C(C.sub.2 H.sub.5).sub.2 CH.sub.2                                                      C.sub.2 H.sub.5                                                                  γ,γ-diethyl-3                                                     ,3-                                                               CH.sub.2 CO dimethyl-1-propyl//                                                           butyric acid                 153                                                                              CH.sub.3                                                                           CH.sub.3                                                                         n-C.sub.3 H.sub.7                                                                 H  H      S CH.sub.2CH                                                                              C(n-C.sub.3 H.sub.7).sub.2 CH(n-                                                       C.sub.2 H.sub.5                                                                  3,3-dimethyl-β,.gamm                                                     a.,γ,4-                                                     C.sub.3 H.sub.7 CH.sub.2 CO                                                               tetrapropyl-1-vinyl//                                                         butyric acid                 154                                                                              H    H  H   H  H      S CH.sub.2CHCH.sub.2                                                                      [C(CH.sub.3).sub.2]2 -                                                                 C.sub.2 H.sub.5                                                                  1-allyl-β,β,.ga                                                     mma.,γ-                                                     CH.sub.2 CO tetramethyl//butyric                                                          acid                         155                                                                              H    H  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  6-Cl   S CH.sub.2CH                                                                              [C(C.sub.2 H.sub.5).sub.2]2 CH-                                                        C.sub.2 H.sub.5                                                                  7-chloro-α,β,.                                                     beta.,γ,γ,4-                                          (C.sub.2 H.sub.5)CO                                                                       4-heptaethyl-1-vinyl//                                                        butyric acid                 156                                                                              H    H  CH.sub.3                                                                          H  4-CH.sub.3                                                                           S                                                                                ##STR104##                                                                             [C(CH.sub.3).sub.2]3 CO                                                                C.sub.2 H.sub.5                                                                  1-ethynyl-α,α                                                     ,β,β,γ,.g                                                     amma.- 4,5-octamethyl//                                                       butyric acid                 157                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   H                                                                                 ##STR105##                                                                          S                                                                                ##STR106##                                                                             CH(C.sub.2 H.sub.5)[C- (C.sub.2                                               H.sub.5)].sub.2 CO                                                                     C.sub.2 H.sub.5                                                                  6-acetoxy-α,α                                                     ,β,β,γ,3-                                                      3,4-octaethyl-1-                                                             (1-propynyl)//butyric                                                         acid                         158                                                                              H    H  CH.sub.3                                                                          CH.sub.3                                                                         7-OCH.sub.3                                                                          S                                                                                ##STR107##                                                                             CH.sub.2 [C(CH.sub.3).sub.3]2                                                          C.sub.2 H.sub.5                                                                  1-cyclobutyl-α,.alp                                                     ha.,β,β-                                                            4,4-hexamethyl-8-                                                             methoxy//butyric acid        159                                                                              H    H  H   H  4-Br   S                                                                                ##STR108##                                                                             CH.sub.2 CH(CH.sub.3)C- (CH.sub.3).su                                         b.2 CO   C.sub.2 H.sub.5                                                                  5-bromo-1-cyclopentyl-                                                        α,α,β-tr                                                     imethyl// butyric acid       160                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H   H  4-n-C.sub.3 H.sub.7                                                                  S                                                                                ##STR109##                                                                             CH.sub.2 CH.sub.2 C(C.sub.2 -                                                 H.sub.5).sub.2 CO                                                                      C.sub.2 H.sub.5                                                                  1-cyclopropyl-α,.al                                                     pha.- diethyl-3,3,dimethy                                                     l- 5-propyl//butyric                                                          acid                         161                                                                              H    H  H   H  7-C.sub.2 H.sub.5                                                                    S                                                                                ##STR110##                                                                             CH.sub.2 CH.sub.2 CH- (CH.sub.3)CO                                                     C.sub.2 H.sub.5                                                                  8-ethyl-α-methyl-1-                                                      phenyl//butyric acid        162                                                                              CH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                          H  5-F    S                                                                                ##STR111##                                                                             [CH(CH.sub.3)].sub.3 CO                                                                C.sub.2 H.sub.5                                                                  6-fluoro-α,β,.                                                     gamma.,3,3,4- hexamethyl-                                                     1-phenyl// butyric acid      163                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H   H  4-CH.sub.3                                                                           S                                                                                ##STR112##                                                                             CH(C.sub.2 H.sub.5)CH.sub.2 CH-                                               (C.sub.2 H.sub.5)CO                                                                    C.sub.2 H.sub.5                                                                  α,γ-diethyl-1                                                     -phenyl- 3,3,5-trimethyl/                                                     / butyric acid               164                                                                              C.sub.2 H.sub.5                                                                    H  H   H  6-NO.sub.2                                                                           S                                                                                ##STR113##                                                                             [CH(CH.sub.3)].sub.3 CO                                                                C.sub.2 H.sub.5                                                                  1-benzyl-3-ethyl-7-                                                           nitro-α,β,.gam                                                     ma.- trimethyl//butyric                                                       acid                         165                                                                              CH.sub.3                                                                           CH.sub.3                                                                         H   H  4-n-C.sub.3 H.sub.7                                                                  S                                                                                ##STR114##                                                                             CH[CH(C.sub.2 - H.sub.5)].sub.2                                                        C.sub.2 H.sub.5                                                                  1-benzyl-α,β-d                                                     iethyl- 3,3-dimethyl-5-                                                       propyl//butyric acid         166                                                                              H    H  H   H  7-OH   S                                                                                ##STR115##                                                                             C(CH.sub.3).sub.2 CH.sub.2 C-                                                 (CH.sub.3).sub.2 CO                                                                    C.sub.2 H.sub.5                                                                  1-benzyl-8-hydroxy-                                                           α,α,γ,.                                                     gamma.-tetramethyl//                                                          butyric acid                 167                                                                              CH.sub.3                                                                           H  CH.sub.3                                                                          H  4-OC.sub.2 H.sub.5                                                                   S                                                                                ##STR116##                                                                             [C(CH.sub.3).sub.2]3 CO                                                                C.sub.2 H.sub.5                                                                  5-ethoxy-α,α,                                                     β,β,γ,.ga                                                     mma.,- 3,4-octomethyl-1-                                                      2-thienyl)// butyric                                                          acid                         168                                                                              C.sub.2 H.sub.5                                                                    H  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  6-Cl   S                                                                                ##STR117##                                                                             CH.sub.2 CH.sub.2 C(C.sub.2 -                                                 H.sub.5).sub.2 CO                                                                      C.sub.2 H.sub.5                                                                  7-chloro-α,α,                                                     3,4,4- pentaethyl-1-                                                          (2-thienyl)// butyric                                                         acid                         __________________________________________________________________________

EXAMPLE 1691-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]Indole-1-Carboxaldehyde (XI; R¹= CH₃, R², R³, R⁴, R⁵ and R⁶ = H, and Y = CO)

A mixture of the starting material, tryptophol (32.2 g, 0.2 mole),acetonyl acetate (23.2 g. 0.2 mole) and 3.2 g of p-toluenesulfonic acidin 500 ml of benzene is refluxed for 11/2 hr. in the presence of aDean-Stark water trap. The benzene solution is washed with 5% sodiumbicarbonate, water, dried and evaporated to afford an oil. The oil issubjected to chromatography on a silica gel column using 10% ethylacetate in benzene as eluent. The acetate,1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol, acetate isobtained as an oil, nmr(CDCl₃) δ 1.52(S,3H), 2.08(S,3H), 4.35(2H).

This acetate is dissolved in 250 ml of methanol and stirred at roomtemperature. To this solution is added dropwise 20 ml of 10N NaOH.Hydrolysis is immediate. Most of the methanol is removed under reducedpressure, and water is added. The mixture is rendered neutral andextracted with chloroform. The chloroform extract is dried andevaporated to afford the primary alcohol,1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol (X; R¹ = CH₃,R², R³, R⁴, R⁵ and R⁶ = H, Y = CH₂ and R¹⁷ = H), m.p. 145°-147° C.,nmr(CDCl₃) δ 1.43(s,3H), 2.68(t, J = 5.5 cps, 2H), 3.65 (d, J = 6 cps,2H), 3.86 (t, J = 5.5 cps, 2H), after crystallization frombenzene-petroleum ether.

N,N-dicyclohexylcarbodiimide (17.36 g, 0.084 mole) is added to a cooled,stirred solution of the above primary alcohol (6.09 g, 0.028 mole) in 63ml of dimethyl sulfoxidebenzene (2:1) containing trifluoroacetic acid(1.12 ml, 0.014 mole) and pyridine (2.24 ml, 0.028 mole). The reactionis stirred at room temperature under nitrogen for 5 hr. The reactionmixture is now diluted with 600 ml of ether, followed by the dropwiseaddition of a solution of oxalic acid (7.56 g) in 21 ml of methanol.After 30 minutes, water (600 ml) is added and the insoluble material iscollected. The organic phase is washed with water (2X), 5% aqueoussodium bicarbonate (2X) and water (2X). After drying (MgSO₄) the organicphase is evaporated to yield an oil. The oil is purified bychromatography on silica gel. Elution with 10% ether in benzene affordsthe title compound as eluate, nmr (CDCl₃) δ 1.59(s,3H), 2.84(t,J = 5.5cps, 2H), 4.15(t, J = 5.5 cps, 2H).

Oxidation of the latter compound with silver oxide according to themethod of Delepine and Bonnet, cited above, affords1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxylic acid, nmr(CDCl₃) δ 1.79(s,3H), 2.83(t,2H), 4.17(t,2H), 9.20(1H), identical to theproduct obtained in Example 4.

By following the procedure of Example 169 but using as starting materialan equivalent amount of the appropriate starting material of formula II,for example, those described in Examples 1 to 168, inclusive, instead oftryptophol, and using an equivalent amount of the appropriateketoalcohol lower alkyl ester of formula VIII, then the acid compoundsof formula I in which R⁷ is hydrogen and Z is hydroxy, for example, therespective products of Examples 1 to 168, inclusive, are obtained.

More specifically exemplified, according to the procedure of Example 169the use of indole-3-ethanethiol and acetonyl acetate affords1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid,identical to the product of Example 3. Similarly, the use of tryptopholand 5-acetoxypentan-2-one affords1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid,identical to the product of Example 2.

EXAMPLE 170N,N,1-Trimethyl-1,3,4,9-Tetrahydropyrano[3,4-b]-indole-1-Acetamide (I;R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O, Y = CH₂ CO and Z =N(CH₃)₂)

To a stirred solution of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g,0.061 mole), prepared as described in Example 1, in dry tetrahydrofuran(300 ml), cooled to -5° C, is added triethylamine (18.5 g, 0.183 mole),followed by ethyl chloroformate (16.6 g, 0.153 mole). The mixture isstirred at -5° C for 2 hr. This mixture, which now contains the mixedanhydride of the above starting material, is added dropwise to a cooled40% aqueous solution of the amine, dimethylamine (225 ml). The resultingmixture is stirred at room temperature for one-half hour. Most of thetetrahydrofuran is evaporated, and the residue partitioned betweenchloroform and water. The organic phase is washed with water, dried oversodium sulfate, and evaporated under reduced pressure. The residue issubjected to chromatography on silica gel. Elution with 20% ethylacetate in benzene, followed by crystallization of the eluate from ethylacetate affords the title compound, m.p. 149°-151° C., γ _(max)^(CHCl).sbsp.3 3375, 1634 cm⁻ ¹.

In the same manner but replacing dimethylamine with an equivalent amountof ammonium hydroxide (concentrated), methylamine (30% aqueoussolution), n-hexylamine (20% aqueous solution), diethylamine (30%aqueous solution), or aniline (20% aqueous solution),

1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p.158°-160° C,

N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p.138°-140° C,

N-(hexyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,n-diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,m.p. 99° C, and

N-phenyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,m.p. 205°-208° C, are obtained respectively.

By following the procedure of Example 170 but using as a startingmaterial an equivalent amount of one of the acid compounds of formula I,described in Examples 2 to 168, inclusive, instead of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and usingan equivalent amount of an appropriate amine such as ammonia or aprimary or secondary amine described in Example 170, then thecorresponding amide compound of formula I ##STR118## is obtained,Examples of such amides are listed as products in Tables III and IVtogether with the appropriate starting material and amine used for thepreparation of the amide. In each case the starting material is noted bythe example in which it is prepared.

                                      TABLE III                                   __________________________________________________________________________           NO. OF THE EXAMPLE   PRODUCT: [PREFIX LISTED BELOW-                          IN WHICH STARTING     1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                        MATERIAL IS           INDOLE-1-(SUFFIX LISTED BELOW)]                   EXAMPLE                                                                             PREPARED     AMINE    PREFIX//SUFFIX                                    __________________________________________________________________________    171   2            CH.sub.3 NH.sub.2                                                                      N,1-dimethyl//propionamide,                                                   m.p. 149-150° C.                           172   2            NH.sub.3 1-methyl//propionamide                            173   2            (CH.sub.3).sub.2 NH                                                                    N,N,1-trimethyl//propionamide                     174   2            n-C.sub.6 H.sub.13 NH.sub.2                                                            N-hexyl-1-methyl//propionamide                    175   2            (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-1-methyl//propionamide                176   4            CH.sub.3 NH.sub.2                                                                      N,1-dimethyl//carboxamide                         177   4            NH.sub.3 1-methyl//carboxamide, m.p. 188-                                              189° C.                                    178   4            (CH.sub.3).sub.2 NH                                                                    N,N,1-trimethyl//carboxamide                      179   4            n-C.sub.6 H.sub.13 NH.sub.2                                                            N-hexyl-1-methyl//carboxamide                     180   4            (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-1-methyl//carboxamide                 181   5            CH.sub.3 NH.sub.2                                                                      N,3-dimethyl-1-ethyl//carboxamide                 182   8                                                                                           ##STR119##                                                                            8-ethyl-1-ethynyl-N-phenyl// carboxamide          183   9            (CH.sub.3).sub.2 NH                                                                    1-cyclopropyl-N,N-dimethyl-4-iso-                                             propyl//carboxamide                               184   11           n-C.sub.16 H.sub.13 NH.sub.2                                                           N-hexyl-1-phenyl//carboxamide                     185   12           (C.sub.2 H.sub.5).sub.2 NH                                                             1-benzyl-3-methyl-N,N,3-tri-                                                  ethyl//carboxamide                                186   14           (CH.sub.3).sub.2 NH                                                                    N,N,1,4-tetramethyl//acetamide                    187   15           CH.sub.3 NH.sub.2                                                                      1-ethyl-N-methyl//acetamide                       188   15           NH.sub.3 1-ethyl//acetamide                                189   15           (CH.sub.3).sub.2 NH                                                                    N,N-dimethyl-1-ethyl//acetamide                   190   15           n-C.sub.16 H.sub.13 NH.sub.2                                                           1-ethyl-N-hexyl//acetamide                        191   15           (C.sub.2 H.sub.5).sub.2 NH                                                             N,N,1-triethyl//acetamide                         192   16           CH.sub.3 NH.sub.2                                                                      N-methyl-1-propyl//acetamide                      193   16           NH.sub.3 1-propyl//acetamide, m.p. 157.5 -                                             160° C                                     194   16           (CH.sub.3).sub.2 NH                                                                    N,N,-dimethyl-1-propyl//acetamide                 195   16           n-C.sub.6 H.sub.13 NH.sub.2                                                            N-hexyl-1-propyl//acetamide                       196   16           (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-1-propyl//acetamide                   197   17           CH.sub.3 NH.sub.2                                                                      1-isopropyl-N-methyl//acetamide                   198   17           NH.sub.3 1-isopropyl//acetamide                            199   17           (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-1-isopropyl//acetamide                200   19           CH.sub.3 NH.sub.2                                                                      N,3-dimethyl-1-propyl//acetamide                  201   19                                                                                          ##STR120##                                                                            3-methyl-N-phenyl-1-propyl// acetamide            202   19           (CH.sub.3).sub.2 NH                                                                    1-propyl-N,N,3-trimethyl//acetamide               203   19           n-C.sub.6 H.sub.13 NH.sub.2                                                            N-hexyl-3-methyl-1-propyl//                                                   acetamide                                         204   19           (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-3-methyl-1-propyl//                                               acetamide                                         205   21           CH.sub.3 NH.sub.2                                                                      N,α,1-trimethyl//acetamide                  206   21           NH.sub.3 α,1-dimethyl//acetamide                     207   21           (CH.sub.3).sub.2 NH                                                                    N,N,α,1-tetramethyl//acetamide              208   21           n-C.sub.6 H.sub.13 NH.sub.2                                                            α,1-dimethyl-N-hexyl//acetamide             209   21           (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-α,1-dimethyl//                                              acetamide                                         210   22           CH.sub.3 NH.sub.2                                                                      1-cyclohexyl-N,α,α-trimethyl//                                    acetamide                                         211   23           (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-1-phenyl//acetamide                   212   26           CH.sub.3 NH.sub.2                                                                      N,8-dimethyl-1-propyl//acetamide                  213   31           NH.sub.3 6-benzyloxy-1-methyl//acetamide                   214   32           (CH.sub.3).sub.2 NH                                                                    1-propyl-N,N,5-trimethyl//                                                    acetamide                                         215   38           n-C.sub.6 H.sub.13 NH.sub.2                                                            1-cyclopropyl-α,α-diethyl-3,3-                                    dimethyl-6-ethoxy-N-hexyl//                                                   acetamide                                         216   43           (CH.sub.3).sub.2 NH                                                                    1-benzyl-N,N,α,α,3-pentamethyl-                                   8-propionoxy//acetamide                           217   46           CH.sub.3 NH.sub.2                                                                      5-iodo-1-isopropyl-N-methyl//                                                 propionamide                                      218   49           NH.sub.3 1-cyclobutyl-3-methyl-8-nitro-                                                α-propyl//propionamide                      219   54           (CH.sub.3).sub.2 NH                                                                    4,4-diethyl-N,N,α,α,β,3-hexa-                                N                                                                             methyl-1-methallyl//propionamide                  220   57           (C.sub.2 H.sub.5).sub.2 NH                                                             N,N-diethyl-5-methoxy-α-methyl-                                         1-phenyl-3-propyl//propionamide                   221   62           CH.sub.3 NH.sub.2                                                                      N-methyl-β-propyl-1-(1-propynyl)-                                        3,3,5-triethyl//propionamide                      222   63                                                                                          ##STR121##                                                                            1-cyclopropyl-α,β-diethyl-6-                                       ethoxy-N-phenyl//propionamide                     223   67           (CH.sub.3).sub.2 NH                                                                    N,N,1-trimethyl//butyramide                       224   67           CH.sub.3 NH.sub.2                                                                      N,1-dimethyl//butyramide                          225   67           NH.sub.3 1-methyl//butyramide                              226   67           n-C.sub.6 H.sub.13 NH.sub.2                                                            N-hexyl-1-methyl//butyramide                      227   70           CH.sub.3 NH.sub.2                                                                      β,γ,γ,4-tetrapropy1-N,3,3-                                   trimethyl-1-vinyl//butyramide                     228   71           (C.sub.2 H.sub.5).sub.2 NH                                                             1-allyl-N,N-diethyl-β,β,γ,.gam                                ma.-                                                                          tetramethyl//butyramide                           229   73           (CH.sub.3).sub.2 NH                                                                    N,N,α,α,β,β,γ,.gam                                ma.,4,5-decamethyl-                                                           1-ethynyl//butyramide                             230   76           NH.sub.3 5-bromo-1-cyclopentyl-α,α,β,-                                2                                                                             trimethyl//butyramide                             231   78           CH.sub.3 NH.sub.2                                                                      8-ethyl-N,α-dimethyl-1-phenyl//                                         butyramide                                        232   80           (C.sub.2 H.sub.5).sub.2 NH                                                             1-phenyl-N,N,α,γ-tetraethyl-                                      3,3,5-trimethyl//butyramide                       233   82           n-C.sub.6 H.sub.13 NH.sub.2                                                            1-benzyl-α,β,-diethyl-3,3-                                         dimethyl-N-hexyl-5-propyl//                                                   butyramide                                        __________________________________________________________________________

                                      TABLE IV                                    __________________________________________________________________________           NO. OF THE EXAMPLE    PRODUCT: [(PREFIX LISTED BELOW-                         IN WHICH STARTING     1,3,4,9-TETRAHYDROTHIOPYRANO-                           MATERIAL IS           [3,4-b]INDOLE-1-(SUFFIX LISTED                   EXAMPLE                                                                              PREPARED      AMINE   BELOW)]PREFIX//SUFFIX                            __________________________________________________________________________    234     3            CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//acetamide                          235     3            NH.sub.3                                                                              1-methyl//acetamide                              236     3            n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//acetamide                      237     3            (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//acetamide, m.p.                                              182-184° C                                238     3            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-methyl//acetamide                  239    129           CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//propionamide                       240    129           NH.sub.3                                                                              1-methyl//propionamide                           241    129           (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//propionamide                    242    129           n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//propionamide                   243    129           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-methyl//propion-                                                amide                                            244     87           CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//carboxamide                        245     87           NH.sub.3                                                                              1-methyl//carboxamide,                           246     87           (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//carboxamide                     247     87           n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//carboxamide                    248     87           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-methyl//carboxamide                249     88           CH.sub.3 NH.sub.2                                                                     N,3-dimethyl-1-ethyl//carboxamide                250     91           NH.sub.3                                                                              8-ethyl-1-ethynyl//carboxamide                   251     92           (CH.sub.3).sub.2 NH                                                                   1-cyclopropyl-N,N-dimethyl-4-iso-                                             propyl//carboxamide                              252     94           n-C.sub.16 H.sub.13 NH.sub.2                                                          N-hexyl-1-phenyl//carboxamide                    253     95           (C.sub.2 H.sub.5).sub.2 NH                                                            1-benzyl-3-methyl-N,N,3-tri-                                                  ethyl//carboxamide                               254     97           (CH.sub.3).sub.2 NH                                                                   N,N,1,4-tetramethyl//acetamide                   255     98           CH.sub.3 NH.sub.2                                                                     1-ethyl-N-methyl//acetamide                      256     98           NH.sub.3                                                                              1-ethyl//acetamide                               257     98           (CH.sub.3).sub.2 NH                                                                   N,N-dimethyl-1-ethyl//acetamide                  258     98           n-C.sub.16 H.sub.13 NH.sub.2                                                          1-ethyl-N-hexyl//acetamide                       259     98           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N,1-triethyl//acetamide                        260     99           CH.sub.3 NH.sub.2                                                                     N-methyl-1-propyl//acetamide                     261     99           NH.sub.3                                                                              1-propyl//acetamide                              262     99           (CH.sub.3).sub.2 NH                                                                   N,N-dimethyl-1-propyl//acetamide                 263     99           n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-propyl//acetamide                      264     99           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-propyl//acetamide                  265    100           CH.sub.3 NH.sub.2                                                                     1-isopropyl-N-methyl//acetamide                  266    100           NH.sub.3                                                                              1-isopropyl//acetamide                           267    100           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-isopropyl//acetamide               268    102           CH.sub.3 NH.sub.2                                                                     N,3-dimethyl-1-propyl//acetamide                 269    102           NH.sub.3                                                                              3-methyl-1-propyl//acetamide                     270    102           (CH.sub.3).sub.2 NH                                                                   1-propyl-N,N,3-trimethyl//                                                    acetamide                                        271    102           n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-3-methyl-1-propyl//                                                   acetamide                                        272    102           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-3-methyl-1-propyl//                                               acetamide                                        273    104           CH.sub.3 NH.sub.2                                                                     N,α,1-trimethyl//acetamide                 274    104           NH.sub.3                                                                              α,1-dimethyl//acetamide                    275    104           (CH.sub.3).sub.2 NH                                                                   N,N,α,1-tetramethyl//acetamide             276    104           n-C.sub.6 H.sub.13 NH.sub.2                                                           α,1-dimethyl-N-hexyl//acetamide            277    104           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-α,1-dimethyl//                                              acetamide                                        278    105           CH.sub.3 NH.sub.2                                                                     1-cyclohexyl-N,α,α-trimethyl//                                    acetamide                                        279    106           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-phenyl//acetamide                  280    109           CH.sub.3 NH.sub.2                                                                     N,8-dimethyl-1-propyl//acetamide                 281    111           NH.sub.3                                                                              6-bromo-1-propyl//acetamide                      282    117           (CH.sub.3).sub.2 NH                                                                   α ,α-diethyl-N,N-dimethyl-8-fluor                                 o-                                                                            1-vinyl//acetamide                               283    121           n-C.sub.6 H.sub.13 NH.sub.2                                                           1-cyclopropyl-α,α-diethyl-3,3-                                    dimethyl-6-ethoxy-N-hexyl//                                                   acetamide                                        284    126           (CH.sub.3).sub.2 NH                                                                   1-benzyl-N,N,α,α,3-pentamethyl-                                   8-propionoxy//acetamide                          285    128           CH.sub.3 NH.sub.2                                                                     1-(2-thienyl)-N,α,α-trimethyl//                                   acetamide                                        286    132           NH.sub.3                                                                              1-cyclobutyl-3-methyl-8-nitro-                                                α-propyl//propionamide                     287    137           (CH.sub.3).sub.2 NH                                                                   4,4-diethyl-N,N,α,α,β,3-                                     hexamethyl-1-methallyl//                                                      propionamide                                     288    140           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-5-methoxy-α-methyl-1-                                       phenyl-3-propyl//propionamide                    289    145           CH.sub.3 NH.sub.2                                                                     N-methyl-β-propyl-1-(1-propynyl)-                                        3,3,5-triethyl//propionamide                     290    146                                                                                          ##STR122##                                                                           1-cyclopropyl-α,β-diethyl-6-                                       ethoxy-N-phenyl//propionamide                    291    150           (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//butyramide                      292    150           CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//butyramide                         293    150                                                                                          ##STR123##                                                                           1-methyl-N-phenyl//butyramide                    294    150           n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//butyramide                     295    153           CH.sub.3 NH.sub.2                                                                     β,γ,γ,4-tetrapropyl-N,3,3-                                   trimethyl-1-vinyl//butyramide                    296    154           (C.sub.2 H.sub.5).sub.2 NH                                                            1-allyl-N,N-diethyl-β,β,γ,.ga                                 mma.-                                                                         tetramethyl//butyramide                          297    155           (CH.sub.3).sub.2 NH                                                                   7-chloro-N,N-dimethyl-α,β,β,.                                 gamma.,γ,-                                                              4,4-heptaethyl-1-ethynyl//butyramide             298    159           NH.sub.3                                                                              5-bromo-1-cyclopentyl-α,α,β-                                 M                                                                             trimethyl//butyramide                            299    161           CH.sub.3 NH.sub.2                                                                     N,α-dimethyl-8-ethyl-1-phenyl//                                         butyramide                                       300    163           (C.sub.2 H.sub.5).sub.2 NH                                                            1-phenyl-N,N,α,γ-tetraethyl-                                      3,3,5-trimethyl//butyramide                      301    165           n-C.sub.6 H.sub.13 NH.sub.2                                                           1-benzyl-α ,β-diethyl-3,3-dimethyl                                 -                                                                             N-hexyl-5-propyl//butyramide                     302    168           CH.sub.3 NH.sub.2                                                                     7-chloro-N-methyl-α,α,3,4,4-                                      pentaethyl-1-(2-thienyl)//                                                    butyramide                                       __________________________________________________________________________

EXAMPLE 303 1-Methyl-1,3,4,9-Tetrahydropyrano[3,4-b]indole-1-Carboxamide(I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O, Y = CO and Z = NH₂)

By following the procedure of Example 1 but using an equivalent amountof pyruvamide instead of ethyl acetoacetate,1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxamide, m.p.188°-189° C. after recrystallization from benzene-hexane, identical withthe product of Example 177, is obtained.

In the same manner but using an equivalent amount of the appropriatestarting material of formula II in place of tryptophol together with theappropriate α-, β-, γ- or δ-ketoamide, the products listed in Tables IIIand IV may be obtained. For example, by using tryptophol (II; R², R³,R⁴, R⁵, R⁶ = H and X' = OH) and the β-ketoamide,N,N-dimethyl-acetoacetamide, in the procedure of this Example,N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,identical with the product of Example 170, is obtained.

EXAMPLE 304 1,9-Dimethyl-1,3,4,9-Tetrahydropyrano[3,4-b]indole-1-AceticAcid (I; R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, X = O, Y = CH₂ COand Z = OH

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (10 g.,0.04 mole), prepared as described in Example 1, in 150 ml. oftetrahydrofuran is added dropwise to a stirred suspension of sodiumhydride (4.4 g. of 55% dispresion) in 200 ml. of tetrahydrofuran. Thismixture is heated at 50° C. with stirring for 2 hr. Methyl iodide (14.2g. 0.1 mole) is added dropwise and heating and stirring is continued fora further 2 hr.

After cooling, water is added until the solution is clear. Thetetrahydrofuran is evaporated off under reduced pressure, the residue ispartition between water and benzene. The aqueous phase is washed oncewith benzene, made acidic with HCl, and extracted with benzene (3x). Theorganic phase is washed with water, dried over sodium sulfate andtreated with charcoal. The organic layer is evaporated. The residue iscrystallized from benzene and then ether-petroleum ether to afford thetitle compound, m.p. 105°-108° C., nmr (CDCl₃) δ 1.73 (S,3H), 2.83 (t, J= 5.5, 2H), 3.0 (2H), 3.68 (3H), 4.08 (t, J = 5.5, 2H), 7.34 (4H), 9.47(1H).

In the same manner but replacing methyl iodide with an equivalent amountof ethyl iodide, or propyl iodide9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid,m.p. 134°-136° C., and1-methyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid,m.p. 120°-122° C., are obtained, respectively. The corresponding ethylester of the latter compound,1-methyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acidethyl ester has m.p. 72°-74° C.

By following the procedure of Example 304 but using the startingmaterial an equivalent amount of the acid compounds of formula I,compounds of formula I in which R⁷ is hydrogen and Z is hydroxy,described in Examples 1 to 168, inclusive, instead of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid, and usingan equivalent amount of an appropriate lower alkyl or lower alkenylhalide, then the corresponding N-alkylated acid compounds of formula Iin which R⁷ is lower alkyl or lower alkenyl are obtained. Examples ofthese latter compounds are listed as products in Tables V and VItogether with the appropriate starting material and alkyl or alkynlhalide used for their preparation. In each case the starting material isnoted by the Example in which it is prepared.

                                      TABLE V                                     __________________________________________________________________________           NO. OF THE EXAMPLE         PRODUCT: [(PREFIX LISTED BELOW-                    IN WHICH STARTING          1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                   MATERIAL IS   ALKYL OR ALKENYL                                                                           INDOLE-1-(SUFFIX LISTED BELOW)]             EXAMPLE                                                                              PREPARED       HALIDE         PREFIX//SUFFIX                           __________________________________________________________________________    305    1             CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-methyl//acetic acid,                                                m.p.103 - 105° C.                    306    1             CH.sub.2 =CHBr                                                                             1-methyl-9-vinyl//acetic acid               307    1             CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                           1-methyl-9-methallyl//acetic acid           308    2             n-C.sub.3 H.sub.7 I                                                                        1-methyl-9-propyl//propionic acid           309    2             CH.sub.3 I   1,9-dimethyl//propionic acid, m.p.                                            129-130° C                           310    2             CH.sub. 2 =CHBr                                                                            1-methyl-9-vinyl//propionic acid            311    2             CH.sub.2 =CHCH.sub.2 Cl                                                                    9-allyl-1-methyl//propionic acid            312    4             CH.sub.3 I   1,9-dimethyl//carboxylic acid               313    4             CH.sub.2 =CHBr                                                                             1-methyl-9-vinyl//carboxylic acid           314    7             CH.sub.3 I   6-hydroxy-1-(1-propenyl)-3,3,9-                                               trimethyl//carboxylic acid                  315    9             CH.sub.3 CH=CHBr                                                                           1-cyclopropyl-4-isopropyl-9-                                                  (1-propenyl)//carboxylic acid               316    11            i-C.sub.3 H.sub.7 I                                                                        9-isopropyl-1-phenyl//carboxylic                                              acid                                        317    15            CH.sub.3 I   1-ethyl-9-methyl//acetic acid               318    15            C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl//acetic acid                    319    15            CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-ethyl//acetic acid                320    15            CH.sub.2 =CHBr                                                                             1-ethyl-9-vinyl//acetic acid                321    16            CH.sub.3 I   9-methyl-1-propyl//acetic acid              322    16            n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl//acetic acid                   323    16            CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-propyl//acetic acid               324    16            CH.sub.2 =C(CH.sub.3)CH.sub.2 Br                                                           9-methallyl-1-propyl//acetic acid           325    17            CH.sub.3 I   9-methyl-1-isopropyl//acetic acid           326    17            CH.sub.2 =CHBr                                                                             1-isopropyl-9-vinyl//acetic acid            327    19            n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl-3-methyl//acetic acid          328    19            CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-3-methyl-1-propyl//acetic                                             acid                                        329    21            CH.sub.3 I   α,1,9-trimethyl//acetic acid          330    21            CH.sub.2 =CHBr                                                                             α,1-dimethyl-1-vinyl//acetic                                            acid                                        331    22            n-C.sub.3 H.sub.7 Cl                                                                       1-cyclohexyl-α,α-dimethyl-9-                                      N                                                                             propyl//acetic acid                         332    27            CH.sub.2 =CHCH.sub.2 I                                                                     9-allyl-1-(2-thienyl)//acetic acid          333    29            CH.sub.3 Cl  1,9-dimethyl-6-methoxy//acetic acid         334    34            CH.sub.2 =CHBr                                                                             6-nitro-1-propyl-9-vinyl//                                                    acetic acid                                 335    40            C.sub.2 H.sub.5 Cl                                                                         α,3-dimethyl-9-ethyl-1-phenyl-                                          4,4,5-tripropyl//acetic acid                336    42            CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-1-benzyl-α,α-diisopr                                      opyl-                                                                         3,3,4,4,5-pentaethyl//acetic acid           337    48            C.sub.2 H.sub.5 I                                                                          7-hydroxy-1-(2-propynyl)-3,6,9-                                               triethyl//propionic acid                    338    49            CH.sub.3 I   1-cyclobutyl-3,9-dimethyl-8-nitro-                                            α-propyl//propionic acid              339    54            CH.sub.2 =C(CH.sub.3)CH.sub.2 Cl                                                           4,4-diethyl-1,9-dimethallyl-α,.alp                                      ha.,β,-                                                                  3-tetramethyl//propionic acid               340    59            CH.sub.2 =CHCH.sub.2 Br                                                                    9-allyl-8-chloro-β,3,3,4,4-                                              pentamethyl-1-(2-thienyl)//                                                   propionic acid                              341    60            CH.sub.2 =CHCl                                                                             1-methyl-6-nitro-α,α,β,                                      β,3-penta-                                                               ethyl-9-vinyl//propionic acid               342    63            C.sub.2 H.sub.5 Cl                                                                         1-cyclopropyl-6-ethoxy-α,β,9-                                      3                                                                             triethyl//propionic acid                    343    67            CH.sub.3 I   1,9-dimethyl//butyric acid                  344    67            CH.sub.2 =CHCH.sub.2 Cl                                                                    9-allyl-1-methyl//butyric acid              345    68            C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl-γ,3-dimethyl//butyric                                       A                                                                             acid                                        346    70            CH.sub.2 =CHBr                                                                             3,3-dimethyl-1,9-divinyl-β,γ,                                      γ,-                                                                     4-tetrapropyl//butyric acid                 347    72            CH.sub.2 =CHBr                                                                             7-chloro-1,9-divinyl-α,β,.bet                                      a.,γ,γ,-                                                          4-heptaethyl//butyric acid                  348    78            C.sub.2 H.sub.5 I                                                                          8,9-diethyl-α-methyl-1-phenyl//                                         butyric acid                                349    82            CH.sub.3 I   1-benzyl-α,β,-diethyl-5-propy                                      l-                                                                            3,3,9-trimethyl//butyric acid               350    85            C.sub.2 H.sub.5 Br                                                                         7-chloro-α,α,3,4,4,9-hexaeth                                      yl-                                                                           1-(2-thienyl)//butyric                      __________________________________________________________________________                                      acid                                    

                                      TABLE VI                                    __________________________________________________________________________           NO. OF THE EXAMPLE         PRODUCT:[(PREFIX LISTED BELOW-1,3,-                IN WHICH STARTING          4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                   MATERIAL IS   ALKYL OR ALKENYL                                                                           INDOLE-1-(SUFFIX LISTED BELOW)]             EXAMPLE                                                                              PREPARED       HALIDE         PREFIX//SUFFIX                           __________________________________________________________________________    351    3             CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-1-methyl//acetic acid               352    3             CH.sub.3 I   1,9-dimethyl//acetic acid                   353    3             CH.sub.2 C(CH.sub.3)CH.sub.2 Br                                                            1-methyl-9-methallyl//acetic                                                  acetic acid                                 354    129           n-C.sub. 3 H.sub.7 I                                                                       1-methyl-9-propyl//propionic                                                  acid                                        355    129           CH.sub.3 I   1,9-dimethyl//propionic acid                356    129           CH.sub.2 CHBr                                                                              1-methyl-9-vinyl//propionic acid            357    129           CH.sub.2 CHCH.sub.2 Cl                                                                     9-allyl-1-methyl//propionic acid            358    87            CH.sub.3 I   1,9-dimethyl//carboxylic acid               359    87            CH.sub.2 CHBr                                                                              1-methyl-9-vinyl//carboxylic                                                  acid                                        360    90            CH.sub.3 I   6-hydroxy-1-(1-propenyl)-3,3,9-                                               trimethyl//carboxylic acid                  361    92            CH.sub.3 CHCHBr                                                                            1-cyclopropyl-4-isopropyl-9-                                                  (1-propenyl)//carboxylic acid               362    94            2-C.sub.3 H.sub.7 I                                                                        9-isopropyl-1-phenyl//carboxylic                                              acid                                        363    98            CH.sub.3 I   1-ethyl-9-methyl//acetic acid               364    98            C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl//acetic acid                    365    98            CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-1-ethyl//acetic acid                366    98            CH.sub.2 CHBr                                                                              1-ethyl-9-vinyl//acetic acid                367    99            CH.sub.3 I   9-methyl-1-propyl//acetic acid              368    99            n-C.sub. 3 H.sub.7 Cl                                                                      1,9-dipropyl//acetic acid                   369    99            CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-1-propyl//acetic acid               370    99            CH.sub.2 C(CH.sub.3)CH.sub.2 Br                                                            9-methallyl-1-propyl//acetic                                                  acid                                        371    100           CH.sub.3 I   9-methyl-1-isopropyl//acetic                                                  acid                                        372    100           CH.sub.2 CHBr                                                                              1-isopropyl-9-vinyl//acetic                                                   acid                                        373    102           n-C.sub. 3 H.sub.7 Cl                                                                      1,9-dipropyl-3-methyl//acetic                                                 acid                                        374    102           CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-3-methyl-1-propyl//                                                   acetic acid                                 375    104           CH.sub.3 I   α,1,9-trimethyl//acetic acid          376    104           CH.sub.2 CHBr                                                                              α,1-dimethyl-1-vinyl//acetic                                            acid                                        377    105           n-C.sub. 3 H.sub.7 Cl                                                                      1-cyclohexyl-α,α-dimethyl-9-                                      N                                                                             propyl//acetic acid                         378    110           CH.sub.2 CHCH.sub.2 I                                                                      9-allyl-1-(2-thienyl)//acetic                                                 acid                                        379    112           CH.sub.3 Cl  1,9-dimethyl-6-methoxy//                                                      acetic acid                                 380    117           CH.sub.2 CHBr                                                                              α,α-diethyl-1,9-divinyl-8-                                        fluoro//acetic acid                         381    123           C.sub.2 H.sub.5 Cl                                                                         α,3-dimethyl-9-ethyl-1-phenyl-                                          4,4,5-tripropyl//acetic                                                       acid                                        382    125           CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-1-benzyl-α,α-                                             diisopropyl-3,3,4,4,5-                                                        pentaethyl//acetic acid                     383    131           C.sub.2 H.sub.5 I                                                                          7-hydroxy-1-(2-propynyl)-                                                     β,β,9-triethyl//propionic                                           acid                                        384    132           CH.sub.3 I   1-cyclobutyl-3,9-dimethyl-8-                                                  nitro-α-propyl//propionic acid        385    137           CH.sub.2 C(CH.sub.3)CH.sub.2 Cl                                                            4,4-diethyl-1,9-dimethallyl-                                                  α,α,β,3-tetramethyl//pr                                      opionic                                                                       acid                                        386    142           CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-8-chloro-β,3,3,4,4-                                              pentamethyl-1-(2-thienyl)//                                                   propionic acid                              387    143           CH.sub.2 CHCl                                                                              1-methyl-6-nitro-α,α,β,                                      β,3-penta-                                                               ethyl-9-vinyl//propionic acid               388    146           C.sub.2 H.sub.5 Cl                                                                         1-cyclopropyl-6-ethoxy-α,β,9-                                      a                                                                             triethyl//propionic acid                    389    150           CH.sub.3 I   1,9-dimethyl//butyric acid                  390    150           CH.sub.2 CHCH.sub.2 Cl                                                                     9-allyl-1-methyl//butyric acid              391    151           C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl-γ,3-dimethyl//                                              butyric acid                                392    153           CH.sub.2 CHBr                                                                              3,3-dimethyl-1,9-divinyl-β,γ,                                      γ,-                                                                     4-tetrapropyl//butyric acid                 393    155           CH.sub.2 CHBr                                                                              7-chloro-1,9-divinyl-α,β,.bet                                      a.,γ,γ,-                                                          4,4-heptaethyl//butyric acid                394    161           C.sub.2 H.sub.5 I                                                                          8,9-diethyl-α-methyl-1-phenyl//                                         butyric acid                                395    165           CH.sub.3 I   1-benzyl-α,β-diethyl-5-propyl                                      -                                                                             3,3,9-trimethyl//butyric acid               396    168           C.sub.2 H.sub.5 Br                                                                         7-chloro-α,α,3,4,4,9-hexaeth                                      yl-                                                                           1-(2-thienyl)//butyric                      __________________________________________________________________________                                      acid                                    

EXAMPLE 397

By following the procedure of Example 304 but using as the startingmaterial an equivalent amount of the ester compounds of formula I inwhich R⁷ is hydrogen and Z is lower alkoxy, obtained prior to hydrolysisin Example 1 and 3 to 168, inclusive, instead of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and usingan equivalent amount of an appropriate lower alkyl or lower alkenylhalide, then the corresponding N-alkylated ester compounds of formula Iin which R⁷ is lower alkyl or lower alkenyl, are obtained.

For example, when following the procedure of Example 304, thereplacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-aceticacid by an equivalent amount of its corresponding ethyl ester, describedin Example 1, and then use the same alkyl halide, methyl iodide, affords1,9-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethylester.

Similarly, the replacement of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by anequivalent amount of1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methylester, described in Example 3, affords1,9-dimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acidmethyl ester.

By following the procedure of Example 170 but using as the startingmaterial an equivalent amount of one of the N-alkylated acid compoundsof formula I, described in Examples 304 to 396, inclusive, instead of1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and usingan equivalent amount of an appropriate amine such as ammonia or aprimary or secondary amine, described in Example 170, then thecorresponding amide compound of formula I in which R⁷ is lower alkyl orlower alkenyl and Z is amino, lower alkyl amino, di(lower)alkylamino orphenylamino, is obtained. Examples of such amides are listed as productsin Tables VII and VIII together with the appropriate starting material,noted by the example in which it is prepared, and the amine used for thepreparation of the amide.

                                      TABLE VII                                   __________________________________________________________________________          NO. OF THE EXAMPLE  PRODUCT: [(PREFIX LISTED BELOW-                           IN WHICH STARTING   1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          MATERIAL IS         INDOLE-1-(SUFFIX LISTED BELOW)]                     EXAMPLE                                                                             PREPARED      AMINE PREFIX//SUFFIX                                      __________________________________________________________________________    398   304          (CH.sub.3).sub.2 NH                                                                  N,N,1,9-tetramethyl//acetamide,                                               ν.sub.max.sup.CHCl  1620, 1070                                             cm.sup.-.sup.1, nmr                                                           (CDCl.sub.3) δ 1.71, 2.76, 2.89, 3.00,                                  3.71                                                399   304          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//acetamide, m.p.                                              136 - 138° C.                                400   304          NH.sub.3                                                                             1,9-dimethyl//acetamide, m.p.                                                 105 - 106° C.                                401   304          n-C.sub.6 H.sub.13 NH.sub.2                                                          1,9-dimethyl-N-hexyl//acetamide                     402   304          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1,9-dimethyl//                                                    acetamide, ν.sub.max.sup.CHCl 3 1630                                       cm.sup.-.sup.1,                                                               nmr (CDCl.sub.3) δ 1.10, 1.74, 2.80,                                    3.97                                                403   305          CH.sub.3 NH.sub.2                                                                    9-allyl-N,1-dimethyl//acetamide                     404   305          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                     acetamide                                           405   309          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//propionamide,                                                m.p. 148 - 150° C                            406   309          (C.sub.2 H.sub.5).sub.2 NH                                                           1,9-dimethyl-N,N-diethyl//                                                    propionamide                                        407   311          NH.sub.3                                                                             9-allyl-1-methyl//propionamide                      408   311          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N-1-trimethyl//                                                     propionamide                                        409   313          CH.sub.3 NH.sub.2                                                                    N,1-dimethyl-9-vinyl//                                                        carboxamide                                         410   314          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-6-hydroxy-1-                                                      (1-propenyl)-3,3,9-trimethyl//                                                carboxamide                                         411   316          n-C.sub.6 H.sub.3 NH.sub.2                                                           N-hexyl-9-isopropyl-1-phenyl//                                                carboxamide                                         412   317          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-ethyl//acetamide                     413   319          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N,1-triethyl//                                                      acetamide                                           414   320          (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-1-ethyl-9-vinyl//                                                acetamide                                           415   321          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-propyl//                                                       acetamide                                           416   323          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N-diethyl-1-propyl//                                                acetamide                                           417   331          CH.sub.3 NH.sub.2                                                                    1-cyclohexyl-9-propyl-N,α,α-                                      trimethyl//acetamide                                418   332          n-C.sub.6 H.sub.13 NH.sub.2                                                          9-allyl-N-hexyl-1-(2-thienyl)//                                               acetamide                                           419   333          (CH.sub.3).sub.2 NH                                                                  6-methoxy-N,N,1,9-tetramethyl//                                               acetamide, m.p. 118 - 120° C.                420   335          CH.sub.3 NH.sub.2                                                                    9-ethyl-1-phenyl-4,4,5-                                                       tripropyl-N,α,3-trimethyl//                                             acetamide                                           421   341          (C.sub.2 H.sub.5).sub.2 NH                                                           N,Nα,α,β,β,3-heptaethyl-1-                              N                                                                             methyl-6-nitro-9-vinyl//                                                      propionamide                                        422   342          (C.sub.2 H.sub.5).sub.2 NH                                                           1-cyclopropyl-6-methoxy-N,N-                                                  α,β,9-pentaethyl-9-vinyl//                                         propionamide                                        423   343          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//butyramide                         424   344          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                     butyramide                                          425   345          NH.sub.3                                                                             1,9-diethyl-γ,3-dimethyl//                                              butyramide                                          426   349          CH.sub.3 NH.sub.2                                                                    1-benzyl-α,β-diethyl-5-propyl-                                     N,3,3,9-tetramethyl//                                                         butyramide                                          __________________________________________________________________________

                                      TABLE VIII                                  __________________________________________________________________________          NO. OF THE EXAMPLE  PRODUCT:[(PREFIX LISTED BELOW-1,3,                        IN WHICH STARTING   4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                          MATERIAL IS         INDOLE-1-(SUFFIX LISTED BELOW)]                     EXAMPLE                                                                             PREPARED      AMINE PREFIX//SUFFIX                                      __________________________________________________________________________    427   352          (CH.sub.3).sub.2 NH                                                                  N,N,1,9-tetramethyl//acetamide,                                               ν.sub.max.sup.CHCl 3 1625 cm.sup.-.sup.1,                                  nmr (CDCl.sub.3),                                                             δ 2.23, 3.65                                  428   352          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//acetamide, m.p.                                              127-128° C.                                  429   352          NH.sub.3                                                                             1,9-dimethyl//acetamide                             430   352          n-C.sub.6 H.sub.13 NH.sub.2                                                          1,9-dimethyl-N-hexyl//acetamide                     431   352          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1,9-dimethyl//                                                    acetamide                                           432   351          CH.sub.3 NH.sub.2                                                                    9-allyl-N,1-dimethyl//acetamide                     433   351          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                     acetamide                                           434   355          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//propionamide                       435   355          (C.sub.2 H.sub.5).sub.2 NH                                                           1,9-dimethyl-N,N-diethyl//                                                    propionamide                                        436   357          NH.sub.3                                                                             9-allyl-1-methyl//propionamide                      437   357          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                     propionamide                                        438   359          CH.sub.3 NH.sub.2                                                                    N,1-dimethyl-9-vinyl//                                                        carboxamide                                         439   360          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-6-hydroxy-1-                                                      (1-propenyl)-3,3,9-trimethyl//                                                carboxamide                                         440   362          n-C.sub.6 H.sub.3 NH.sub.2                                                           N-hexyl-9-isopropyl-1-phenyl//                                                carboxamide                                         441   363          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-ethyl//                                                        acetamide                                           442   365          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N,1-triethyl//                                                      acetamide                                           443   366          (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-1-ethyl-9-vinyl//                                                acetamide                                           444   367          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-propyl//acetamide                    445   369          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N-diethyl-1-propyl//                                                acetamide                                           446   377          CH.sub.3 NH.sub.2                                                                    1-cyclohexyl-9-propyl-N,α,α-                                      trimethyl//acetamide                                447   378          n-C.sub.6 H.sub.13 NH.sub.2                                                          9-allyl-N-hexyl-1-(2-thienyl)//                                               acetamide                                           448   379          (CH.sub.3).sub.2 NH                                                                  6-methoxy-N,N,1,9-tetramethyl//                                               acetamide                                           449   381          CH.sub.3 NH.sub.2                                                                    9-ethyl-1-phenyl-4,4,5-                                                       tripropyl-N,α,3-trimethyl//                                             acetamide                                           450   387          (C.sub.2 H.sub.5).sub.2 NH                                                           N,Nα,α,β,β,3-heptaethyl-1-                              O                                                                             methyl-6-nitro-9-vinyl//                                                      propionamide                                        451   388          (C.sub.2 H.sub.5).sub.2 NH                                                           1-cyclopropyl-6-ethoxy-N,N-                                                   α,β,9-pentaethyl//propionamide           452   389          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//butyramide                         453   390          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//                                                     butyramide                                          454   391          NH.sub.3                                                                             1,9-diethyl-γ,3-dimethyl//                                              butyramide                                          455   395          CH.sub.3 NH.sub.2                                                                    1-benzyl-α,β-diethyl-5-propyl-                                     N,3,3,9-tetramethyl//butyramide                     __________________________________________________________________________

EXAMPLE 4566-Hydroxy-1-Methyl-1,3,4,9-Tetrahydropyano[3,4-b]Indole-1-Acetic Acid(I; R¹ = CH₃, R², R³, R⁴, R⁵ and R⁷ = H, R⁶ = 6-OH, X = O, Y = CH₂ COand Z = OH)

A mixture of6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid(5.3 g., 0.015 mole), prepared as described in Example 31, in 250 ml. ofanhydrous ethanol, and 1.1 g. of 10% palladium on carbon is stirred atroom temperature under a hydrogen atmosphere until no more hydrogen isbeing taken up by the reaction mixture. The catalyst is removed byfiltration through diatomaceous earth (Celite) and the filtrateconcentrated. The residue is recrystallized from ethanol-benzene toafford the title compound, m.p, 170°-171° C.

The corresponding benzylamine salt is prepared by the mixing ofequimolar ethereal solutions of benzylamine and the above product. Theresulting solid is recrystallized from acetonitrile to afford6-hydroxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acidbenzylamine salt, m.p. 191°-193° C. The corresponding acetate isprepared by allowing a mixture of the title compound and a five molarexcess of acetic anhydride in pyridine solution to stand for 24 hr.Dilution of the mixture with water extraction with ether andrecrystallization of the extract residue from benzene-petroleum ether,affords 6-acetoxy-1-methyl-1,3,4,9-tetrahydro[3,4-b]indole-1-aceticacid, identical with the product of Example 30.

Table IX provides further examples of the compounds of this invention.The remarks relating to procedure, starting material and product appliedto Table I are applicable also to Table IX. Note also that startingmaterials of both formulae II and IIa are utilized.

                                      TABLE IX                                    __________________________________________________________________________     ##STR124##                                                                          ##STR125##                                                                                           ##STR126##                                                                                   ##STR127##                       __________________________________________________________________________          R.sup.2                                                                          R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                          R.sup.6                                                                              X R.sup.1                                                                             Y    R.sup.16                                                                          PREFIX//SUFFIX                    __________________________________________________________________________    457   H  H   CH.sub.3                                                                          H  H      O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   4-methyl-1-propyl//                                                           acetic acid, m.p.                                                             191 - 195° C.              458   H  H   H   H  5-CH.sub.3                                                                           O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   6-methyl-1-propyl//                                                           acetic acid, m.p.                                                             126 - 129° C.              459   H  H   H   H  4-i-C.sub.3 H.sub.7                                                                  O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5-isopropyl-1-propyl//                                                        acetic acid, m.p.                                                             164.5 - 165° C.            460   H  H   H   H  4-Cl   O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5-chloro-1-propyl//                                                           acetic acid, m.p.                                                             166 - 169° C.              461   H  H   H   H  6-OCH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7-methoxy-1-propyl//                                                          acetic acid, m.p.                                                             164 - 166° C.              462   H  H   CH.sub.3                                                                          H  H      O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-4-methyl//                                                            acetic acid, m.p.                                                             153 - 156° C.,                                                         (Isomer A), m.p.                                                              132 - 133° C. (Isomer                                                  B)                                463   H  H   H   H  4-Cl   O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5-chloro-1-methyl//                                                           acetic acid, m.p.                                                             183 - 184° C.              464   H  H   H   H  4-C.sub.2 H.sub.5                                                                    O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5-ethyl-1-propyl//                                                            acetic acid, m.p.                                                             130 - 131° C.              465   H  CH.sub.3                                                                          H   H  H      O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-3-methyl//                                                            acetic acid, m.p.                                                             147 - 148° C.,                                                         (Isomer A), m.p.                                                              145 - 146° C.,                                                         (Isomer B)                        466   H  H   H   H  4-CH.sub.3                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-5-methyl//                                                            acetic acid, m.p.                                                             170 - 172° C.              467   H  H   H   H  4-CH.sub.3                                                                           O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1,5-dimethyl//acetic                                                          acid, m.p. 150 - 151°                                                  C.                                468   H  H   H   H  4-Cl   O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5-chloro-1-ethyl//                                                            acetic acid, m.p.                                                             154 - 157° C.              469   H  H   CH.sub.3                                                                          H  H      O t-C.sub.4 H.sub.9                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-t-butyl-4-methyl//                                                          acetic acid, m.p.                                                             179 - 181° C.              470   H  H   H   H  4-OCH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5-methoxy-1-propyl//                                                          acetic acid, m.p.                                                             148 - 151° C.              471   H  H   H   H  7-CH.sub.3                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-8-methyl//                                                            acetic acid, m.p.                                                             160 - 161° C.              472   H  H   CH.sub.3                                                                          H  7-CH.sub.3                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   4,8-dimethyl-1-ethyl//                                                        acetic acid, m.p.                                                             129 - 131° C.              473   H  H   CH.sub.3                                                                          H  7-CH.sub.3                                                                           O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1,4,8-trimethyl//                                                             acetic acid, m.p.                                                             157 - 159° C.              474   H  H   H   H  7-Cl   O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-chloro-1-ethyl//                                                            acetic acid, m.p.                                                             168 - 171° C.              475   H  H   H   H  6-Cl   O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7-chloro-1-ethyl//                                                            acetic acid, m.p.                                                             182 - 183° C.              476   H  H   H   H  6-Cl   O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7-chloro-1-propyl//                                                           acetic acid, m.p.                                                             182 - 183° C.              477   H  H   H   H  7-C.sub.2 H.sub.5                                                                    O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1,8-diethyl//acetic                                                           acid, m.p. 145 - 148°                                                  C.                                478   H  H   H   H  7-OCH.sub.3                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-8-methoxy//                                                           acetic acid, m.p.                                                             132° C.                    479   H  H   H   H                                                                                 ##STR128##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5,8-dimethyl-1-ethyl// acetic                                                 acid, m.p. 175 - 176°                                                  C.                                480   H  H   H   H                                                                                 ##STR129##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5,8-dichloro-1-ethyl// acetic                                                 acid, m.p. 168 - 169°                                                  C.                                481   H  H   H   H                                                                                 ##STR130##                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7,8-dichloro-1-propyl acetic                                                  acid                              482   H  H   H   H                                                                                 ##STR131##                                                                          O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5,7-dichloro-1-methyl acetic                                                  acid                              483   H  H   H   H                                                                                 ##STR132##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-chloro-1-ethyl 5-methyl//ace                                                tic  acid                         484   H  H   H   H                                                                                 ##STR133##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5-chloro-1-ethyl-8- methyl//ac                                                etic acid                         485   H  H   CH.sub.3                                                                          H                                                                                 ##STR134##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7-bromo-1,5-diethyl- 4-methyl/                                                /acetic acid                      486   H  H   H   H                                                                                 ##STR135##                                                                          O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7-chloro-1,8-dimethyl acetic                                                  acid                              487   H  H   CH.sub.3                                                                          H                                                                                 ##STR136##                                                                          O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1,4-dimethyl-5,7,8- trichloro/                                                /acetic  acid                     488   H  H   H   H                                                                                 ##STR137##                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-propyl-5,6,7,8- tetramethoxy                                                // acetic acid                    489   H  H   H   H                                                                                 ##STR138##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-chloro-1-ethyl-5- methoxy//a                                                cetic acid                        490   H  H   CH.sub.3                                                                          H                                                                                 ##STR139##                                                                          O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7,8-dichloro-1- methyl-5-metho                                                xy// acetic acid                  491   H  H   H   H                                                                                 ##STR140##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-5,8-di- methoxy//aceti                                                c acid m.p. 167 - 169°                                                 C.                                492   CH.sub.3                                                                         H   H   H                                                                                 ##STR141##                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-chloro-5-fluoro-3- methyl-1-                                                propyl// acetic acid              493   H  H   H   H                                                                                 ##STR142##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7,8-dichloro-5- fluoro-1-ethyl                                                // acetic acid                    494   C.sub.2 H.sub.5                                                                  H   CH.sub.3                                                                          H                                                                                 ##STR143##                                                                          O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    3-ethyl-5-trifluoro-                                                         methyl-1,4,8- trimethyl//aceti                                                c  acid                           495   H  H   H   H  6-CF.sub.3                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-7-trifluoro-                                                          methyl//acetic acid,                                                          m.p. 185 - 187° C.         496   H  H   CH.sub.3                                                                          H  7-CF.sub.3                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-4-methyl-8-                                                           trifluoromethyl//                                                             acetic acid                       497   H  H   C.sub.2 H.sub.5                                                                   H                                                                                 ##STR144##                                                                          O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1,6-dimethyl-4-ethyl-                                                         8-nitro//acetic acid              498   CH.sub.3                                                                         H   H   H                                                                                 ##STR145##                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-chloro-3-methyl-5-  nitro-1-                                                propyl// acetic acid              499   H  H   H   H  5-SH   O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   6-mercapto-1-methyl//                                                         acetic acid                       500   H  H   CH.sub.3                                                                          H  7-SCH.sub.3                                                                          O CH.sub.3                                                                            CH.sub.2 -                                                                         C.sub.2 H.sub.5                                                                   1,4-dimethyl-8-methyl-                                               CH.sub.2 CO                                                                            thio//propionic acid              501   H  H   H   H  6-SC.sub.2 H.sub.5                                                                   O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-7-ethylthio//                                                         acetic acid                       502   H  H   H   H  4-NH.sub.2                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   5-amino-1-ethyl//                                                             acetic acid                       503   H  H   H   H  6-NH.sub.2                                                                           O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7-amino-1-ethyl//                                                             acetic acid                       504   H  H   H   H  4-SO.sub.2 NH.sub.2                                                                  O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-propyl-5-sulfamoyl//                                                        acetic acid                       505   H  H   H   H  6-SO.sub.2 NH.sub.2                                                                  O CH.sub.3                                                                            CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-methyl-7-sulfamoyl//                                                        acetic acid                       506   H  H   H   H  H      O                                                                                ##STR146##                                                                         CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-cyclopropyl//acetic  acid,                                                  m.p. 128 - 129° C.         507   H  H   H   H  H      O                                                                                ##STR147##                                                                         CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-benzyl//acetic acid,  m.p.                                                  139 - 141° C.              508   H  H   H   H  5-F    O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-6-fluoro//                                                            acetic acid, m.p.                                                             125 - 126° C.              509   H  H   CH.sub.3                                                                          H  6-Cl   O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7-chloro-1-ethyl-                                                             4-methyl//acetic acid                                                         m.p. 141 - 143° C.         510   H  H   H   H  6-F    O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-7-fluoro//                                                            acetic acid, m.p.                                                             164 - 166° C.              511   H  H   CH.sub.3                                                                          H  7-Cl   O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-chloro-1-ethyl-                                                             4-methyl//acetic acid,                                                        m.p. 157 - 163° C.         512   H  H   CH.sub.3                                                                          H  7-C.sub.2 H.sub.5                                                                    O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1,8-diethyl-4-methyl//                                                        acetic acid, m.p.                                                             125 - 130° C.              513   H  H   H   H  7-n-C.sub.3 H.sub.7                                                                  O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-8-propyl//                                                            acetic acid, m.p.                                                             111 - 114° C.              514   H  H   H   H  7-(CH.sub.3).sub.2 -                                                                 O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-8-isopropyl//                                 CH                      acetic acid, m.p.                                                             165 - 167° C.              515   H  H   H   H  7-n-C.sub.4 H.sub.9                                                                  O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-butyl-1-ethyl//                                                             acetic acid, nmr                                                              (CDCl.sub.3) δ 1.0 (t,                                                  J=7 ,6H), 6.9 - 7.11                                                          (m,3H)                            516   H  H   H   H  7-sec- O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-sec-butyl-1-ethyl//                                 C.sub.4 H.sub.9         acetic acid, m.p.                                                             135 - 137° C.              517   H  H   H   H  7-(CH.sub.3).sub.2 -                                                                 O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-8-isobutyl//                                  CHCH.sub.2              acetic acid, nmr                                                              (CDCl.sub.3)                                                                  δ 0.9 (m,9H), 7.0 -                                                     7.5                                                                           (m,3H)                            518   H  H   H   H  7-tert-                                                                              O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-tert-butyl-1-ethyl//                                C.sub.4 H.sub.9         acetic acid, m.p.                                                             169 - 170° C.              519   H  H   CH.sub.3                                                                          H                                                                                 ##STR148##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-4,5,8-trimethyl//                                                     acetic acid, m.p. 167 -                                                       168° C.                    520   H  H   H   H                                                                                 ##STR149##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7,8-dichloro-1-ethyl//                                                        acetic acid, m.p. 112 -                                                       117° C.                    521   H  H   H   H                                                                                 ##STR150##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-chloro-1-ethyl-7-  methyl//a                                                cetic acid,  m.p. 117 -                                                       120° C.                    522   H  H   H   H                                                                                 ##STR151##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7-chloro-1-ethyl-8-  methyl//a                                                cetic acid,  m.p. 119 -                                                       123° C.                    523   H  H   H   H                                                                                 ##STR152##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-7-fluoro-8-  methyl//a                                                cetic acid,  m.p. 158 -                                                       160° C.                    524   H  H   H   H  7-C.sub.2 H.sub.5                                                                    O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-ethyl-1-propyl//                                                            acetic acid, m.p.                                                             103 - 105° C.              525   H  H   H   H  7-n-C.sub.3 -                                                                        O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1,8-dipropyl//acetic                                   H.sub.7                acid, m.p. 109° C.         526   H  H   H   H                                                                                 ##STR153##                                                                          O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   7-chloro-8-methyl-1-  propyl//                                                acetic acid,  m.p. 156 -                                                      158° C.                    527   H  H   H   H                                                                                 ##STR154##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-cyclopropyl-1-ethyl//                                                       acetic acid, m.p. 153 -                                                       154° C.                    528   H  H   H   H                                                                                 ##STR155##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   cyclopentyl-1-ethyl//  acetic                                                 acid, m.p. 137 -  139°                                                 C.                                529   H  H   H   H                                                                                 ##STR156##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   8-cyclohexyl-1-ethyl//                                                        acetic acid, m.p. 156 -                                                       159° C.                    530   H  H   H   H                                                                                 ##STR157##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                   1-ethyl-8-phenyl//  acetic                                                    acid, m.p.  184 -187°                                                  C.                                __________________________________________________________________________

We claim:
 1. A process for preparing a compound of the formula Ia##STR158##in which R¹ is selected from the group consisting of loweralkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyland 2-thienyl, R², R³, R⁴ and R⁵ are the same or different and are eachselected from the group consisting of hydrogen and lower alkyl, R^(6a),R^(6b), R^(6c), and R^(6d) are the same or different and selected fromthe group consisting of hydrogen, lower alkyl, lower cycloalkyl,hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, phenyl, nitro,halo, mercapto, lower alkylthio, trifluoromethyl, amino and sulfamoyl,R⁷ is selected from the group consisting of hydrogen, lower alkyl andlower alkenyl, X is selected from the group consisting of oxy and thio,Y is selected from the group consisting of carbonyl, ##STR159##in whicheach of R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ is hydrogen or lower alkyl, and Zis hydroxy or lower alkoxy comprising: reacting a compound of theformula IIa ##STR160##in which R², R³, R⁴, R⁵, R⁷, R^(6a), R^(6b),R^(6c), R^(6d), and R⁷ are as defined herein and X' is hydroxy ormercapto with a compound of formula ##STR161##in which R¹, Y and Z areas defined herein, in the presence of an acid catalyst.
 2. The processof claim 1 in which the compound of formula IIa is reacted with acompound of formula ##STR162##in which R¹ and Y are as defined thereinand Z is lower alkoxy, and the corresponding compound of formula Ia inwhich Z is lower alkoxy is obtained.
 3. The process of claim 1 in whichthe compound of formula Ia in which Z is lower alkoxy is hydrolyzed togive the corresponding compound of formula Ia in which Z is hydroxy.